Tetracyclic compounds as dgk inhibitors

ABSTRACT

The present application provides tetracyclic compounds that modulate the activity of diacylglycerol kinase (DGK), which are useful in the treatment of various diseases, including cancer.

TECHNICAL FIELD

The present invention provides tetracyclic compounds that modulate theactivity of diacylglycerol kinase (DGK) and are useful in the treatmentof diseases related to diacylglycerol kinase, including cancer.

BACKGROUND

Diacylglycerol kinases (DGKs) are a family of enzymes that regulate manybiological processes, including cellular proliferation, migration,immunity and pathogenesis of diseases such as cancer. In mammaliansystems, there are ten DGK family members classified into five subtypesbased on shared common domains (Sakane F. et al., Int. J. Mol. Sci.,2020. 21: p 6794-6829). The diverse and specific cellular function ofindividual DGK isoforms is regulated through their tissue restrictedexpression, localization within cells and interactions with regulatoryproteins (Joshi, R. P. and Koretzky, G. A., Int. J. Mol. Sci., 2013. 14:p 6649-6673).

In T lymphocytes, DGKα and ζ are the dominant DGK isoforms expressed(Krishna, S. and Zhong, X.-P., Front Immunol., 2013. 4:178).Specifically, in response to T cell receptor (TCR) activation,phospholipase Cγ1 (PLCγ1) hydrolyzes membrane phospholipid PIP2 toproduce diacylglycerol (DAG) (Krishna, S. and Zhong, X.-P., FrontImmunol., 2013. 4:178; Riese, M. J. et al., Front Cell Dev Biol., 2016.4:108). In turn, DAG functions as a second messenger to recruit RasGRP1and PKCθ to the cell membrane and thereby initiates multiple downstreamsignaling events resulting in T cell activation. To preventhyperactivation of T cells, DGKα and ζ tightly regulate the levels ofintracellular DAG by phosphorylating DAG to produce phosphatidic acid(PA). Both mouse and human cell line genetic studies support theimportant regulatory role of DGKα and ζ in T cell activation. Knockoutor depletion of DGKα and ζ has been reported to enhance T cellactivation, cytokine production and proliferation. Furthermore, knockoutof both DGKα and ζ show even greater T-cell activation over individualknockouts, indicating a non-redundant role of these two isoforms (Riese,M. J. et al., Cancer Res., 2013. 73: p 3566-3577; Jung, I.-Y. et al.,Cancer Res., 2018. 78: p 4692-4703). Thus, DGKα and ζ, by regulatingcellular DAG levels link lipid metabolism and intracellular signalingcascades and function as key regulators of T cell activation.

Cytotoxic T lymphocytes (CTLs) are a major component of the adaptiveimmune system that recognize and kill cells with bacterial or viralinfections, or cells displaying abnormal proteins, such as tumorantigens. However, cancer cells can evolve to utilize multiplemechanisms that mimic peripheral immune tolerance to avoid immunesurveillance and killing by CTLs. Such mechanisms include downregulationof antigen presentation, suppression of T cell function throughincreased expression of inhibitory molecules, as well as increasedproduction of immunosuppressive proteins in the tumor microenvironment(Speiser, D. E. et al., Nat. Rev. Immunol., 2016. 16: p. 599-611,Gonzalez H. et al., Genes & Dev., 2018. 32: p 1267-1284). Immunecheckpoint therapy (ICT) by blocking inhibitory molecules such asPD(L)-1 and CTLA4, can restore T cell activity and have been clinicallyuseful in treating many different types of cancers. However, onlysubsets of patients respond to ICT due to primary or acquired resistance(Sharma, P. et al., Cell. 2017. 168: p 707-723). Thus, despite thesignificant recent clinical successes of immunotherapies to treatcancer, resistance remains a challenge (Sharma, P., et al., CancerDiscov., 2021. 11: p 838-857).

Overexpression of DGKα and ζ has been observed in tumor infiltratinglymphocytes (TILs) from human tumors and proposed to suppress T cellfunction. Importantly, significant immune-mediated antitumor activityhas been shown in DGKα and DGKζ deficient mouse models (Merida, I. etal., Adv. Biol. Regul., 2017. 63: p 22-31, Prinz, P. U. et al., J.Immunol., 2012. 188: p 5990-6000). Furthermore, DGKα and DGKζ deficientT cells are resistant to several immunosuppressive factors within thetumor microenvironment such as TGFβ, PGE2 and adenosine, and to other Tcell inhibitory pathways such as PD(L)-1 mediated immune suppression(Riese, M. J. et al., Cancer Res., 2013. 73: p 3566-77; Jung, I.-Y. etal. (2018) Cancer Res., 2018. 78: p 4692-4703; Arranz-Nicolas, J. etal., Cancer Immunol. Immunother., 2018. 67: p 965-980; Riese, M. J. etal., Front. Cell Dev. Biol., 2016. 4:108). Thus DGKα and DGKζ areattractive targets as immunotherapies alone or in combination withcurrent ICT therapies such as PD(L)-1 and CTLA4. By targeting T celllipid metabolism, DGKα and DGKζ inhibition can potentially restoreantitumor immunity in subsets of patient who have primary or acquiredimmune resistance and are consequently refractory to current ICTs. Inaddition to its function in T lymphocytes, DGKα and DGKζ, by regulatingDAG level in cancer cells, have also been reported to directlycontribute to cancer proliferation, migration, invasion and survival.Thus, DGK inhibition may have direct antitumor effect by interferingwith tumor intrinsic oncogenic survival pathways (Cooke, M. andKaznietz, M. G., Sci. Signal., 2022. 15:eabo0264).

Compounds in this application may have selective activities towards oneor both DGKα and DGKζ. These DGK inhibitors alone or in combination withother therapeutic agent(s) can be used in treatment of cancer.

SUMMARY

The present invention relates to, inter alia, compounds of Formula I:

or pharmaceutically acceptable salts thereof, wherein constituentmembers are defined herein.

The present invention further provides pharmaceutical compositionscomprising a compound of Formula I, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

The present invention further provides methods of inhibiting an activityof diacylglycerol kinase (DGK), comprising contacting the kinase with acompound of Formula I, or a pharmaceutically acceptable salt thereof.

The present invention further provides methods of treating a disease ora disorder associated with expression or activity of a diacylglycerolkinase (DGK) in a patient by administering to a patient atherapeutically effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.

The present invention further provides a compound of Formula I, or apharmaceutically acceptable salt thereof, for use in any of the methodsdescribed herein.

The present invention further provides use of a compound of Formula I,or a pharmaceutically acceptable salt thereof, for the preparation of amedicament for use in any of the methods described herein.

DETAILED DESCRIPTION

The present application provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   is a single or double bond;    -   W is CR⁷, C(O), N, or NR⁷;    -   X is CR⁸, C(O), N, or NR⁸.    -   Y is CR⁹ or N;    -   Z is CR¹⁰ or N;    -   wherein no more than 2 of W, X, Y, and Z can be N or a        substituted N;    -   n is 0, 1, or 2;    -   each R² is independently selected from halo, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl,        5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN, NO₂,        OR^(a2), NHOR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),        C(O)NR^(c2)(OR^(a2)), C(O)OR^(a2), OC(O)R^(b2),        OC(O)NR^(c2)R^(d2), NR^(c2), NR^(c2)NR^(c2)R^(d2),        NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2),        C(═NR^(e2))R^(b2), C(═NR^(e2))NR^(c2)R^(d2),        NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))R^(b2),        NR^(c2)S(O)R^(b2), NR^(c2)S(O)NR^(c2)R^(d2), NR^(c2)S(O)₂R^(b2),        NR^(c2)S(O)(═NR^(e2))R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),        S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), S(O)₂NR^(c2)R^(d2),        OS(O)(═NR^(e2))R^(b2), and OS(O)₂R^(b2), wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6        membered heteroaryl, and 4-7 membered heterocycloalkyl of R² are        each optionally substituted with 1, 2, 3, or 4 independently        selected R^(M) substituents;    -   each R^(a2), R^(c2), and R^(d2) is independently selected from        H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 membered        heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆        alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 membered        heterocycloalkyl)-C₁₋₆ alkyl-;    -   or, any R^(c2) and R^(d2) attached to the same N atom, together        with the N atom to which they are attached, form a 5-6 membered        heteroaryl or a 4-7 membered heterocycloalkyl group;    -   each R^(b2) is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl,        5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,        phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-7 membered        heterocycloalkyl)-C₁₋₆ alkyl-;    -   each R^(e2) is independently selected from H, OH, CN, C₁₋₆        alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆        alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered        heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,        C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆        alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-;    -   R³ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered        heteroaryl, and 4-7 membered heterocycloalkyl-, wherein the C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6        membered heteroaryl, and 4-7 membered heterocycloalkyl of R³ are        each optionally substituted with 1, 2, 3, or 4 independently        selected R^(M) substituents;    -   R⁵ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered        heteroaryl, 4-7 membered heterocycloalkyl, wherein the C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6        membered heteroaryl, and 4-7 membered heterocycloalkyl of R⁵ are        each optionally substituted with 1, 2, 3, or 4 independently        selected R^(M) substituents;    -   R⁷ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, —C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆        alkyl-, CN, NO₂, OR^(a7), SR^(a7), NHOR^(a7), C(O)R^(b7),        C(O)NR^(c7)R^(d7), C(O)NR^(c7)(OR^(a7)), C(O)OR^(a7),        OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7),        NR^(c7)NR^(c7)R^(d7) NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7),        NR^(c7)C(O)NR^(c7)R^(d7), C(═NR^(e7))R^(b7),        C(═NR⁷)NR^(c7)R^(d7), C(═NOR^(a7))R^(b7), C(═NOR^(a7))OR^(a7),        NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)C(═NR^(e7))R^(b7),        NR^(c7)S(O)R^(b7), NR^(c7)S(O)NR^(c7)R^(d7), NR^(c7)S(O)₂R^(b7),        NR^(c7)S(O)(═NR^(e7))R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7),        S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7), S(O)₂NR^(c7)R^(d7),        OS(O)(═NR^(e7))R^(b7), and OS(O)₂R^(b7), wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl- of R⁷ are each optionally        substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently        selected R^(7A) substituents;    -   each R^(a7), R^(c7), and R^(d7) is independently selected from        H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀        aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl- of R^(a7), R^(c7) and R^(d7) are        each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8        independently selected R^(7A) substituents;    -   or, any R^(c7) and R^(d7) attached to the same N atom, together        with the N atom to which they are attached, form a 5-10 membered        heteroaryl or a 4-10 membered heterocycloalkyl group, wherein        the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl        group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8        independently selected R^(7A) substituents;    -   each R^(b7) is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl- of R^(b7) are each optionally        substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently        selected R^(7A) substituents;    -   each R^(e7) is independently selected from H, OH, CN, C₁₋₆        alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-;    -   each R^(7A) is independently selected from halo, oxo, C₁₋₆        alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,        C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a71), SR^(a71),        NHOR^(a71), C(O)R^(b71), C(O)NR^(c71)R^(d71),        C(O)NR^(c71)(OR^(a71)), C(O)OR^(a71), OC(O)R^(b71),        OC(O)NR^(c71)R^(d71), NR^(c71)R^(d71), NR^(c71)R^(d71),        NR^(c71)R^(d71), NR^(c71)C(O)R^(b71), NR^(c71)C(O)OR^(a71),        NR^(c71)C(O)NR^(c71)R^(d71), C(═NR^(e71))R^(b71),        C(═NR^(e71))NR^(c71)R^(d71), C(═NOR^(a71))R^(b71),        C(═NOR^(a71))OR^(a71), NR^(c71)C(═NR^(e71))NR^(c71)R^(d71),        NR^(c71)C(═NR^(e71))R^(b71), NR^(c71)S(O)R^(b71),        NR^(c71)S(O)NR^(c71)R^(d71), NR^(c71)S(O)₂R^(b71),        NR^(c71)S(O)(═NR^(e71))R^(b71), NR^(c71)S(O)₂NR^(c71)R^(d71),        S(O)R^(b71), S(O)NR^(c71)R^(d71), S(O)₂R^(b71),        S(O)₂NR^(c71)R^(d71), OS(O)(═NR^(e71))R^(b71), and        OS(O)₂R^(b71), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,        and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(7A) are        each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8        independently selected R^(M) substituents;    -   each R^(a71), R^(c71), and R^(d71) is independently selected        from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,        and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a71), R^(c71) and        R^(d71) are each optionally substituted with 1, 2, 3, 4, 5, 6,        7, or 8 independently selected R^(M) substituents;    -   or, any R^(c71) and R^(d71) attached to the same N atom,        together with the N atom to which they are attached, form a 5-10        membered heteroaryl or a 4-10 membered heterocycloalkyl group,        wherein the 5-10 membered heteroaryl or 4-10 membered        heterocycloalkyl group is optionally substituted with 1, 2, 3,        4, 5, 6, 7, or 8 independently selected R^(M) substituents;    -   each R^(b71) is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl- of R^(b71) are each optionally        substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently        selected R^(M) substituents;    -   each R^(e71) is independently selected from H, OH, CN, C₁₋₆        alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-;    -   R⁸ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, —C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆        alkyl-, CN, NO₂, OR^(a8), SR^(a8), NHOR^(a8), C(O)R^(b8),        C(O)NR^(c8)R^(d8), C(O)NR^(c8)(OR^(a8)), C(O)OR^(a8),        OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8),        NR^(c8)NR^(c8)R^(d8), NR^(c8)C(O)R^(b8), NR^(c8)C(O)OR^(a8),        NR^(c8)C(O)NR^(c8)R^(d8), C(═NR^(e8))R^(b8),        C(═NR^(e8))NR^(c8)R^(d8), C(═NOR^(a8))R^(b8),        C(═NOR^(a8))OR^(a8), NR^(c8)C(═NR^(e8))NR^(c8)R^(d8),        NR^(c8)C(═NR^(e8))R^(e8), NR^(c8)S(O)R^(b8),        NR^(c8)S(O)NR^(c8)R^(d8), NR^(c8)S(O)₂R^(b8),        NR^(c8)S(O)(═NR^(e8))R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8),        S(O)R^(b8), S(O)NR^(c8)R^(d8), S(O)₂R^(b8), S(O)₂NR^(c8)R^(d8),        OS(O)(═NR^(c8))R^(b8), and OS(O)₂R^(b8), wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl- of R⁸ are each optionally        substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently        selected R^(8A) substituents;    -   each R^(a8), R^(b8), and R^(d8) is independently selected from        H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀        aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl- of R^(a8), R^(c8) and R^(d8) are        each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8        independently selected R^(8A) substituents;    -   or, any R^(c8) and R^(d8) attached to the same N atom, together        with the N atom to which they are attached, form a 5-10 membered        heteroaryl or a 4-10 membered heterocycloalkyl group, wherein        the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl        group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8        independently selected R^(8A) substituents;    -   each R^(b8) is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl- of R^(b8) are each optionally        substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently        selected R^(8A) substituents;    -   each R^(e8) is independently selected from H, OH, CN, C₁₋₆        alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-;    -   each R^(8A) is independently selected from halo, oxo, C₁₋₆        alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,        C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a81), SR^(a81),        NHOR^(a81), C(O)R^(b81), C(O)NR^(c81)R^(d81),        C(O)NR^(c81)(OR^(a81)), C(O)OR^(a81), OC(O)R^(b81),        OC(O)NR^(c81)R^(d81), NR^(c8)R^(d81), NR^(c81)R^(d81),        NR^(c81)R^(d81), NR^(c81)C(O)R^(b81), NR^(c81)C(O)OR^(b81),        NR^(c81)C(O)NR^(c81)R^(d81), C(═NR^(e81))R^(b81),        C(═NR^(e81))NR^(c81)R^(d81), C(═NOR^(a81))R^(b81),        C(═NOR^(a81))OR^(a81), NR^(c81)C(═NR^(e81))NR^(c81)R^(d81),        NR^(c81)C(═NR^(e81))R^(b81), NR^(c81)S(O)R^(b81),        NR^(c81)S(O)NR^(c81)R^(d81), NR^(c81)S(O)₂R^(b81),        NR^(c81)S(O)(═NR^(e81))R^(b81), NR^(c81)S(O)₂NR^(c81)R^(d81),        S(O)R^(b81), S(O)NR^(c81)R^(d81), S(O)₂R^(b81),        S(O)₂NR^(c81)R^(d81), OS(O)(═NR^(e81))R^(b81), and        OS(O)₂R^(b81), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,        and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(8A) are        each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8        independently selected R^(M) substituents;    -   each R^(a81), R^(c81), and R^(d81) is independently selected        from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,        and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a81), R^(c81) and        R^(d81) are each optionally substituted with 1, 2, 3, 4, 5, 6,        7, or 8 independently selected R^(M) substituents;    -   or, any R^(c81) and R^(d81) attached to the same N atom,        together with the N atom to which they are attached, form a 5-10        membered heteroaryl or a 4-10 membered heterocycloalkyl group,        wherein the 5-10 membered heteroaryl or 4-10 membered        heterocycloalkyl group is optionally substituted with 1, 2, 3,        4, 5, 6, 7, or 8 independently selected R^(M) substituents;    -   each R^(b81) is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl- of R^(b81) are each optionally        substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently        selected R^(M) substituents;    -   each R^(e81) is independently selected from H, OH, CN, C₁₋₆        alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-;    -   R⁹ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,        (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a9),        SR^(a9), NHOR^(a9), C(O)R^(b9), C(O)NR^(c9)R^(d9),        C(O)NR^(c9)(OR^(a9)), C(O)OR^(a9), OC(O)R^(b9),        OC(O)NR^(c9)R^(d9), NR^(c99)R^(d99), NR^(c9)NR^(c9)R^(d9),        NR^(c9)C(O)R^(b9), NR^(c9)(O)OR^(a9), NR^(c9)C(O)NR^(c9)R^(d9),        C(═NR^(e9))R^(b9), C(═NR^(e9))NR^(c9)R^(d9), C(═NOR^(a9))R^(b9),        C(═NOR^(a9))OR^(a9), NR^(c9)C(═NR^(e9))NR^(c9)R^(d9),        NR^(c9)(═NR^(e9))R^(b9), NR^(c9)S(O)R^(b9),        NR^(c9)S(O)NR^(c9)R^(d9), NR^(c9)S(O)₂R^(b9),        NR^(c9)S(O)(═NR^(e9))R^(b9), NR^(c9)S(O)₂NR^(c9)R^(d9),        S(O)NR^(c9), S(O)NR^(c9)R^(d9), S(O)₂R^(b9), S(O)₂NR^(c9)R^(d9),        OS(O)(═NR^(e9))R^(b9), and OS(O)₂R^(b9), wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,        and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R⁹ are each        optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8        independently selected R^(9A) substituents;    -   each R^(a9), R^(c9), and R^(d9) is independently selected from        H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀        aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl- of R^(a9), R^(c9) and R^(d9) are        each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8        independently selected R^(9A) substituents;    -   or, any R^(c9) and R^(d9) attached to the same N atom, together        with the N atom to which they are attached, form a 5-10 membered        heteroaryl or a 4-10 membered heterocycloalkyl group, wherein        the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl        group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8        independently selected R^(9A) substituents;    -   each R^(c99) and R^(d99) is independently selected from H, C₁₋₆        alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,        and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a9),        R^(c9) and R^(d9) are each optionally substituted with 1, 2, 3,        4, 5, 6, 7, or 8 independently selected R^(9A) substituents;    -   each R^(b9) is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl- of R^(b9) are each optionally        substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently        selected R^(9A) substituents;    -   each R^(e9) is independently selected from H, OH, CN, C₁₋₆        alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-;    -   each R^(9A) is independently selected from halo, oxo, C₁₋₆        alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,        C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a91), SR^(a91),        NHOR^(a91), C(O)R^(b91), C(O)NR^(c91)R^(d91),        C(O)NR^(c91)(OR^(a91)), C(O)OR^(a91), OC(O)R^(b91),        OC(O)NR^(c91)R^(d91), NR^(c91)R^(d91), NR^(c91)NR^(c91)R^(d91)        NR^(c91)C(O)R^(b91), NR^(c91)C(O)OR^(a91),        NR^(c91)C(O)NR^(c91)R^(d91), C(═NR^(c91))R^(b91),        C(═NR^(c91))NR^(c91)R^(d91), C(═NOR^(a91))R^(b91),        C(═NOR^(a91))OR^(a91), NR^(c91)C(═NR^(e91))NR^(c91)R^(d91),        NR^(c91)C(═NR^(e91))R^(b91), NR^(c91)S(O)R^(b91),        NR^(c91)S(O)NR^(c91)R^(d91), NR^(c91)S(O)₂R^(b91),        NR^(c91)S(O)(═NR^(e91))R^(b91), NR^(c91)S(O)₂NR^(c91)R^(d91),        S(O)R^(b91), S(O)NR^(c91)R^(d91), S(O)₂R^(b91),        S(O)₂NR^(c91)R^(d91), OS(O)(═NR^(e91))R^(b91), and        OS(O)₂R^(b91), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,        and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(9A) are        each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8        independently selected R^(M) substituents;    -   each R^(a91), R^(c91), and R^(d91) is independently selected        from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,        and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a91), R^(c91) and        R^(d91) are each optionally substituted with 1, 2, 3, 4, 5, 6,        7, or 8 independently selected R^(M) substituents;    -   or, any R^(c91) and R^(d91) attached to the same N atom,        together with the N atom to which they are attached, form a 5-10        membered heteroaryl or a 4-10 membered heterocycloalkyl group,        wherein the 5-10 membered heteroaryl or 4-10 membered        heterocycloalkyl group is optionally substituted with 1, 2, 3,        4, 5, 6, 7, or 8 independently selected R^(M) substituents;    -   each R^(b91) is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl- of R^(b91) are each optionally        substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently        selected R^(M) substituents;    -   each R^(e91) is independently selected from H, OH, CN, C₁₋₆        alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-;    -   R¹⁰ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆        alkyl-, CN, NO₂, OR^(a10), SR^(a10), NHOR^(a10), C(O)R^(b10),        C(O)NR^(c10)R^(d10), C(O)NR^(c10)(OR^(a10)), C(O)OR^(a10),        OC(O)R^(b10), OC(O)NR^(c10)R^(d10), NR^(c10)R^(d10),        NR^(c10)NR^(c10)R^(d10), NR^(c10)C(O)R^(b10),        NR^(c10)C(O)OR^(a10), NR^(c10)C(O)NR^(c10)R^(d10),        C(═NR^(e10))R^(b10), C(═NR^(e10))NR^(c10)R^(d10),        C(═NOR^(a10))R^(b10), C(═NOR^(a10))OR^(a10),        NR^(c10)C(═NR^(e10))NR^(c10)R^(d10),        NR^(c10)C(═NR^(e10))R^(b10), NR^(c10)S(O)R^(b10),        NR^(c10)S(O)NR^(c10)R^(d10), NR^(c10)S(O)₂R^(b10),        NR^(c10)S(O)(═NR^(e10))R^(b10), NR^(c10)S(O)₂NR^(c10)R^(d10),        S(O)R^(b10), S(O)NR^(c10)R^(d10), S(O)₂R^(b10),        S(O)₂NR^(c10)R^(d10), OS(O)(═NR^(e10))R^(b10), and        OS(O)₂R^(b10), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,        and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R¹⁰ are each        optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8        independently selected R^(10A) substituents;    -   each R^(a10), R^(c10), and R^(d10) is independently selected        from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,        and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a10), R^(c10) and        R^(d10) are each optionally substituted with 1, 2, 3, 4, 5, 6,        7, or 8 independently selected R^(10A) substituents;    -   or, any R^(c10) and R^(d10) attached to the same N atom,        together with the N atom to which they are attached, form a 5-10        membered heteroaryl or a 4-10 membered heterocycloalkyl group,        wherein the 5-10 membered heteroaryl or 4-10 membered        heterocycloalkyl group is optionally substituted with 1, 2, 3,        4, 5, 6, 7, or 8 independently selected R^(10A) substituents;    -   each R^(b10) is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl- of R^(b10) are each optionally        substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently        selected R^(10A) substituents;    -   each R^(e10) is independently selected from H, OH, CN, C₁₋₆        alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-;    -   each R^(10A) is independently selected from halo, oxo, C₁₋₆        alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,        C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a101), SR^(a101),        NHOR^(a101), C(O)R^(b101), C(O)NR^(c101)R^(d101),        C(O)NR^(c101)(OR^(a101)), C(O)OR^(a101), OC(O)R^(b101),        OC(O)NR^(c101)R^(d101), NR^(c101)R^(d101),        NR^(c101)NR^(c101)R^(d101), NR^(c101)C(O)R^(b101),        NR^(c101)C(O)OR^(a101), NR^(c101)C(O)NR^(c101)R^(d101),        C(═NR^(c101))R^(b101), C(═NR^(c101))NR^(c101)R^(d101),        C(═NOR^(a101))R^(b101), C(═NOR^(a101))OR^(a101),        NR^(c101)C(═NR^(c101))NR^(c101)R^(d101),        R^(c101)C(═NR^(c101))R^(b101), NR^(c101)S(O)R^(b101),        NR^(c101)S(O)NR^(c101)R^(d101), NR^(c101)S(O)₂R^(b101),        NR^(c101)S(O)(═NR^(e101))R^(b101),        NR^(c101)S(O)₂NR^(c101)R^(d101), S(O)R^(b101),        S(O)NR^(c101)R^(d101), S(O)₂R^(b101), S(O)₂NR^(c101)R^(d101),        OS(O)(═NR^(e101))R^(b101), and OS(O)₂R^(b101), wherein the C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,        5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl- of R^(10A) are each optionally        substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently        selected R^(M) substituents;    -   each R^(a101), R^(c101), and R^(d101) is independently selected        from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,        C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆        alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,        wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,        C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a101), R^(c101) and        R^(d101) are each optionally substituted with 1, 2, 3, 4, 5, 6,        7, or 8 independently selected R^(M) substituents;    -   or, any R^(c101) and R^(d101) attached to the same N atom,        together with the N atom to which they are attached, form a 5-10        membered heteroaryl or a 4-10 membered heterocycloalkyl group,        wherein the 5-10 membered heteroaryl or 4-10 membered        heterocycloalkyl group is optionally substituted with 1, 2, 3,        4, 5, 6, 7, or 8 independently selected R^(M) substituents;    -   each R^(b101) is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl- of R^(b101) are each optionally        substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently        selected R^(M) substituents;    -   each R^(e101) is independently selected from H, OH, CN, C₁₋₆        alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-;    -   L¹ is C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₃₋₆ cycloalkyl,        or 4-6 membered heterocycloalkyl;    -   Cy¹ is a C₆₋₁₀ aryl or 5-10 membered heteroaryl, wherein the        C₆₋₁₀ aryl and 5-10 membered heteroaryl are each optionally        substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently        selected R¹ substituents;    -   each R¹¹ is independently selected from halo, oxo, C₁₋₆ alkyl,        C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a11), SR^(a11),        NHOR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11),        C(O)NR^(c11)(OR^(a11)), C(O)OR^(a11), OC(O)R^(b11),        OC(O)NR^(c11)R^(d11), NR^(c11)R^(d11), NR^(c11)R^(c11)R^(d11),        NR^(c11)C(O)R^(b11), NR^(c11)C(O)OR^(a11),        NR^(c11)C(O)NR^(c11)R^(d11), C(═NR^(e11))R^(b11),        C(═NR^(e11))NR^(c11)R^(d11),        NR^(c11)C(═NR^(e11))NR^(c11)R^(d11),        NR^(c11)C(═NR^(e11))R^(b11), NR^(c11)S(O)R^(b11),        NR^(c11)S(O)NR^(c11)R^(d11), NR^(c11)S(O)₂R^(b11),        NR^(c11)S(O)(═NR^(e11))R^(b11), NR^(c11)S(O)₂NR^(c11)R^(d11),        S(O)R^(b11), S(O)NR^(c11)R^(d11), S(O)₂R¹¹,        S(O)₂NR^(c11)R^(d11), OS(O)(═NR^(e11))R^(b11), and        OS(O)₂R^(b11), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,        and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R¹¹ are each        optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8        independently selected R^(11A) substituents;    -   each R^(a11), R^(c11), and R^(d11) is independently selected        from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,        and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a11), R^(c11) and        R^(d11) are each optionally substituted with 1, 2, 3, 4, 5, 6,        7, or 8 independently selected R^(11A) substituents;    -   or, any R^(c11) and R^(d11) attached to the same N atom,        together with the N atom to which they are attached, form a 5-10        membered heteroaryl or a 4-10 membered heterocycloalkyl group,        wherein the 5-10 membered heteroaryl or 4-10 membered        heterocycloalkyl group is optionally substituted with 1, 2, 3,        4, 5, 6, 7, or 8 independently selected R^(11A) substituents;    -   each R^(b11) is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl- of R^(b11) are each optionally        substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently        selected R^(11A) substituents;    -   each R^(e11) is independently selected from H, OH, CN, C₁₋₆        alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-;    -   each R^(11A) is independently selected from halo, C₁₋₆ alkyl,        C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇        cycloalkyl, 5-6 membered heteroaryl, 4-7 membered        heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆        alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7 membered        heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a111),        C(O)NR^(c111)R^(d111), C(O)OR^(a111), NR^(c111)R^(d111),        S(O)NR^(c111)R^(d111), S(O)₂R^(b111), S(O)₂NR^(c111)R^(d111),        and OS(O)₂R^(b111), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7        membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇        cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-,        and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-, of R^(11A) are        each optionally substituted with 1, 2, 3, or 4 independently        selected R^(M) substituents;    -   each R^(a111), R^(c111), and R^(d111) is independently selected        from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 membered        heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆        alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 membered        heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered        heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,        C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆        alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl- of        R^(a111), R^(c111) and R^(d111) are each optionally substituted        with 1, 2, 3, or 4 independently selected R^(M) substituents;    -   or, any R^(c111) and R^(d111) attached to the same N atom,        together with the N atom to which they are attached, form a 5-6        membered heteroaryl or a 4-7 membered heterocycloalkyl group,        wherein the 5-6 membered heteroaryl or 4-7 membered        heterocycloalkyl group is optionally substituted with 1, 2, 3,        or 4 independently selected R^(M) substituents;    -   each R^(b111) is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl,        5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,        phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-7 membered        heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered        heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,        C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆        alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl- of        R^(b111) are each optionally substituted with 1, 2, 3, or 4        independently selected R^(M) substituents;    -   R¹² is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆        alkyl-, CN, NO₂, OR^(a12), SR^(a12), NHOR^(a12), C(O)R^(b12),        C(O)NR^(c12)R^(d12), C(O)NR^(c12)(OR^(a12)), C(O)OR^(a12),        OC(O)R^(b12), OC(O)NR^(c12)R^(d12), NR^(c12)R^(d12),        NR^(c12)NR^(c12)R^(d12), NR^(c12)C(O)R^(b12),        NR^(c12)C(O)OR^(a12), NR^(c12)C(O)NR^(c12)R^(d12),        C(═NR^(e12))R^(b12), C(═NR^(e12))NR^(c12)R^(d12),        NR^(c12)C(═NR^(e12))NR^(c12)R^(d12),        NR^(c12)C(═NR^(e12))R^(b12), NR^(c12)S(O)R^(b12),        NR^(c12)S(O)NR^(c12)R^(d12), NR^(c12)S(O)₂R^(b12),        NR^(c12)S(O)(═NR^(e12))R^(b12), NR^(c12)S(O)₂NR^(c12)R^(d12),        S(O)R^(b12), S(O)NR^(c12)R^(d12), S(O)₂R^(b12),        S(O)₂NR^(c12)R^(d12), OS(O)(═NR^(e12))R^(b12), and        OS(O)₂R^(b12), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,        and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R² are each        optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8        independently selected R^(12A) substituents;    -   each R^(a12), R^(c12), and R^(d12) is independently selected        from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,        and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a12), R^(c12) and        R^(d12) are each optionally substituted with 1, 2, 3, 4, 5, 6,        7, or 8 independently selected R^(12A) substituents;    -   or, any R^(c12) and R^(d12) attached to the same N atom,        together with the N atom to which they are attached, form a 5-10        membered heteroaryl or a 4-10 membered heterocycloalkyl group,        wherein the 5-10 membered heteroaryl or 4-10 membered        heterocycloalkyl group is optionally substituted with 1, 2, 3,        4, 5, 6, 7, or 8 independently selected R^(12A) substituents;    -   each R^(b12) is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl- of R^(b12) are each optionally        substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently        selected R^(12A) substituents;    -   each R^(e12) is independently selected from H, OH, CN, C₁₋₆        alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-;    -   each R^(12A) is independently selected from halo, C₁₋₆ alkyl,        C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a121), SR^(a121),        NHOR^(a121), C(O)R^(b121), C(O)NR^(c121)R^(d121),        C(O)NR^(c121)(OR^(a121)), C(O)OR^(a121), OC(O)R^(b121),        OC(O)NR^(c121)R^(d121), NR^(c121)R^(d121),        NR^(c121)R^(c121)R^(d121), NR^(c121)C(O)R^(b121),        NR^(c121)C(o)OR^(a121), NR^(c121)C(O)NR^(c121)R^(d121),        C(═NR^(e121))R^(b121), C(═NR^(e121))NR^(c121)R^(d121),        NR^(c121)C(═NR^(e121))NR^(c121)R^(d121),        NR^(c121)C(═NR^(e121))R^(b121), NR^(c121)S(O)R^(b121),        NR^(c121)S(O)NR^(c121)R^(d121), NR^(c121)S(O)₂R^(b121),        NR^(c121)S(O)(═NR^(e121))R^(b121),        NR^(c121)S(O)₂NR^(c121)R^(d121), S(O)R^(b121),        S(O)NR^(c121)R^(d121), S(O)₂R^(b121), S(O)₂NR^(c121)R^(d121),        OS(O)(═NR^(e121))R^(b121), and OS(O)₂R^(b121), wherein the C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,        5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl- of R^(12A) are each optionally        substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently        selected R^(12B) substituents;    -   each R^(a121), R^(c121), and R^(d121) is independently selected        from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,        and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(a121), R^(c121) and        R^(d121) are each optionally substituted with 1, 2, 3, 4, 5, 6,        7, or 8 independently selected R^(12B) substituents;    -   or, any R^(c121) and R^(d121) attached to the same N atom,        together with the N atom to which they are attached, form a 5-10        membered heteroaryl or a 4-10 membered heterocycloalkyl group,        wherein the 5-10 membered heteroaryl or 4-10 membered        heterocycloalkyl group is optionally substituted with 1, 2, 3,        4, 5, 6, 7, or 8 independently selected R^(12B) substituents;    -   each R^(b121) is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl- of R^(b121) are each optionally        substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently        selected R^(12B) substituents;    -   each R^(e121) is independently selected from H, OH, CN, C₁₋₆        alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-;    -   each R^(12B) is independently selected from halo, C₁₋₆ alkyl,        C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇        cycloalkyl, 5-6 membered heteroaryl, 4-7 membered        heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆        alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7 membered        heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a122),        C(O)NR^(c122)R^(d122), C(O)OR^(a122), NR^(c122)R^(d122),        S(O)NR^(c122)R^(d122), S(O)₂R^(b122), S(O)₂NR^(c122)R^(d122),        and OS(O)₂R^(b122), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7        membered heterocycloalkyl phenyl-C₁₋₆ alkyl-, C₃₋₇        cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-,        and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-, of R^(12B) are        each optionally substituted with 1, 2, 3, or 4 independently        selected R^(M) substituents;    -   each R^(a122), R^(c122), and R^(d122) is independently selected        from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 membered        heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆        alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 membered        heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered        heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,        C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆        alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl- of        R^(a122), R^(c122) and R^(d122) are each optionally substituted        with 1, 2, 3, or 4 independently selected R^(M) substituents;    -   or, any R^(c122) and R^(d122) attached to the same N atom,        together with the N atom to which they are attached, form a 5-6        membered heteroaryl or a 4-7 membered heterocycloalkyl group,        wherein the 5-6 membered heteroaryl or 4-7 membered        heterocycloalkyl group is optionally substituted with 1, 2, 3,        or 4 independently selected R^(M) substituents;    -   each R^(b122) is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl,        5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,        phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-7 membered        heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered        heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,        C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆        alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl- of        R^(b122) are each optionally substituted with 1, 2, 3, or 4        independently selected R^(M) substituents; and    -   each R^(M) is independently selected from H, OH, halo, oxo, CN,        C(O)OH, NH₂, NO₂, SF₅, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,        C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇        cycloalkyl, 5-6 membered heteroaryl, 4-7 membered        heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆        alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 membered        heterocycloalkyl)-C₁₋₆ alkyl-.

In some embodiments, W is CR⁷, N, or NR⁷.

In some embodiments, W is CR⁷.

In some embodiments, W is N.

In some embodiments, W is NR⁷.

In some embodiments, R⁷ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments, R⁷ is selected from H and C₁₋₆ alkyl.

In some embodiments, R⁷ is selected from H and C₁₋₃ alkyl.

In some embodiments, R⁷ is H.

In some embodiments, W is CH, N, or NH.

In some embodiments, W is CH.

In some embodiments, W is NH.

In some embodiments, X is CR⁸ or C(O).

In some embodiments, X is CR⁸.

In some embodiments, X is C(O).

In some embodiments, R⁸ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, —C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, and OR^(a8), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁸ are each optionally substituted with1, 2, 3, or 4 independently selected R^(8A) substituents.

In some embodiments, R⁸ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, and OR, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7membered heterocycloalkyl)-C₁₋₆ alkyl- of R⁸ are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(8A)substituents.

In some embodiments, R⁸ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl-, CN, and OR^(a8),wherein C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl,C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl- of R⁸ are each optionally substituted with 1, 2, 3, or4 independently selected R^(8A) substituents.

In some embodiments, R⁸ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, 5-6 membered heteroaryl, CN, and OR^(a8), wherein C₁₋₆ alkyland 5-6 membered heteroaryl of R⁸ are each optionally substituted with1, 2, 3, or 4 independently selected R^(8A) substituents.

In some embodiments, each R^(a8), R^(b8), R^(c8), and R^(d8) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl.

In some embodiments, each R^(a8) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments, R⁸ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, 5-6 membered heteroaryl, CN, and OR^(a8), wherein C₁₋₆ alkyland 5-6 membered heteroaryl of R⁸ are each optionally substituted with1, 2, 3, or 4 independently selected R^(8A) substituents; and

-   -   each R^(a8) is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments, each R^(8A) is independently selected from halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and CN.

In some embodiments, each R^(8A) is independently selected from C₁₋₆alkyl and CN.

In some embodiments, each R^(8A) is independently selected from C₁₋₃alkyl and CN.

In some embodiments, R⁸ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, 5-6 membered heteroaryl, CN, and OR^(a8), wherein C₁₋₆ alkyland 5-6 membered heteroaryl of R⁸ are each optionally substituted with1, 2, 3, or 4 independently selected R^(8A) substituents independentlyselected from C₁₋₆ alkyl and CN; and

-   -   each R^(a8) is independently selected from H and C₁₋₆ alkyl.

In some embodiments, R⁸ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, 5-6 membered heteroaryl, CN, and OR^(a8), wherein C₁₋₆ alkyland 5-6 membered heteroaryl of R⁸ are each optionally substituted with1, 2, 3, or 4 independently selected R^(8A) substituents independentlyselected from C₁₋₃ alkyl and CN; and

-   -   each R^(a8) is independently selected from H and C₁₋₆ alkyl.

In some embodiments, R⁸ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, 5-6 membered heteroaryl, CN, and OR^(a8), wherein C₁₋₆ alkyland 5-6 membered heteroaryl of R⁸ are each optionally substituted with1, 2, 3, or 4 independently selected R^(8A) substituents independentlyselected from methyl and CN; and

-   -   each R^(a8) is independently selected from H and methyl.

In some embodiments, R⁸ is selected from H, fluoro, methyl, cyanomethyl,cyano, methoxy, and methylpyrazolyl.

In some embodiments, Y is CR⁹.

In some embodiments, Y is N.

In some embodiments, R⁹ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments, R⁹ is selected from H and C₁₋₆ alkyl.

In some embodiments, R⁹ is selected from H and C₁₋₃ alkyl.

In some embodiments, R⁹ is H.

In some embodiments, Y is CH.

In some embodiments, Z is CR¹⁰.

In some embodiments, Z is N.

In some embodiments, R¹⁰ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments, R¹⁰ is selected from H and C₁₋₆ alkyl.

In some embodiments, R¹⁰ is selected from H and C₁₋₃ alkyl.

In some embodiments, R¹⁰ is H.

In some embodiments, Z is CH.

In some embodiments, Y and Z are each CH.

In some embodiments, n is 0.

In some embodiments, n is 1.

In some embodiments, n is 2.

In some embodiments, each R² is independently selected from halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments, each R² is independently selected from C₁₋₆ alkyl.

In some embodiments, each R² is independently selected from C₁₋₃ alkyl.

In some embodiments, each R² is methyl.

In some embodiments, R³ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments, R³ is selected from H and C₁₋₆ alkyl.

In some embodiments, R³ is selected from H and C₁₋₃ alkyl.

In some embodiments, R³ is C₁₋₆ alkyl.

In some embodiments, R³ is C₁₋₃ alkyl.

In some embodiments, R³ is methyl.

In some embodiments, R⁵ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl of R⁵ are each optionally substituted with 1,2, 3, or 4 independently selected R^(M) substituents.

In some embodiments, R⁵ is selected from H and C₁₋₆ alkyl, wherein theC₁₋₆ alkyl of R⁵ is optionally substituted with 1, 2, 3, or 4independently selected R^(M) substituents.

In some embodiments, R⁵ is selected from H and C₁₋₃ alkyl, wherein theC₁₋₃ alkyl of R⁵ is optionally substituted with 1, 2, 3, or 4independently selected R^(M) substituents.

In some embodiments, R⁵ is selected from H, methyl, and ethyl, whereinthe methyl and ethyl of R⁵ are each optionally substituted with 1, 2, 3,or 4 independently selected R^(M) substituents.

In some embodiments, each R^(M) is independently selected from OH, halo,oxo, CN, C(O)OH, NH₂, NO₂, SF₅, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, and C₁₋₆haloalkyl.

In some embodiments, each R^(M) is independently selected from C₁₋₆alkoxy.

In some embodiments, each R^(M) is independently selected from C₁₋₃alkoxy.

In some embodiments, each R^(M) is independently selected from methoxy.

In some embodiments, R⁵ is selected from methyl and methoxyethyl.

In some embodiments, L¹ is C₁₋₃ alkyl.

S In some embodiments, L¹ is CH.

In some embodiments, Cy¹ is phenyl or 5-6 membered heteroaryl, whereinthe phenyl and 5-6 membered heteroaryl of Cy¹ are each optionallysubstituted with 1, 2, 3, or 4 independently selected R¹¹ substituents.

In some embodiments, Cy¹ is phenyl, which is optionally substituted with1, 2, 3, or 4 independently selected R¹¹ substituents.

In some embodiments, each R¹¹ is independently selected from halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments, each R¹¹ is independently selected from halo.

In some embodiments, each R¹¹ is fluoro.

In some embodiments, Cy¹ is fluorophenyl.

In some embodiments, Cy¹ is 4-fluorophenyl.

In some embodiments, R¹² is phenyl or 5-6 membered heteroaryl, whereinthe phenyl and 5-6 membered heteroaryl of R² are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(12A)substituents.

In some embodiments, R¹² is phenyl, which is optionally substituted with1, 2, 3, or 4 independently selected R^(12A) substituents.

In some embodiments, each R^(12A) is independently selected from halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments, each R^(12A) is independently selected from halo.

In some embodiments, each R^(12A) is fluoro.

In some embodiments, R¹² is fluorophenyl.

In some embodiments, R¹² is 4-fluorophenyl.

In some embodiments, Cy¹ and R¹² are each 4-fluorophenyl.

In some embodiments:

-   -   Cy¹ is phenyl or 5-6 membered heteroaryl, wherein the phenyl and        5-6 membered heteroaryl of Cy¹ are each optionally substituted        with 1, 2, 3, or 4 independently selected R¹¹ substituents; and    -   R¹² is phenyl or 5-6 membered heteroaryl, wherein the phenyl and        5-6 membered heteroaryl of R¹² are each optionally substituted        with 1, 2, 3, or 4 independently selected R^(12A) substituents.

In some embodiments:

-   -   Cy¹ is phenyl, which is optionally substituted with 1, 2, 3, or        4 independently selected R¹¹ substituents; and    -   R¹² is phenyl, which is optionally substituted with 1, 2, 3, or        4 independently selected R^(12A) substituents.

In some embodiments:

-   -   Cy¹ is phenyl, which is optionally substituted with 1 or 2        independently selected R¹¹ substituents; and    -   R¹² is phenyl, which is optionally substituted with 1 or 2        independently selected R^(12A) substituents.

In some embodiments:

-   -   Cy¹ is phenyl or 5-6 membered heteroaryl, wherein the phenyl and        5-6 membered heteroaryl of Cy¹ are each optionally substituted        with 1, 2, 3, or 4 independently selected R¹¹ substituents;    -   R¹² is phenyl or 5-6 membered heteroaryl, wherein the phenyl and        5-6 membered heteroaryl of R¹² are each optionally substituted        with 1, 2, 3, or 4 independently selected R^(12A) substituents;    -   each R¹¹ is independently selected from halo, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; and    -   each R^(12A) is independently selected from halo, C₁₋₆ alkyl,        C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments:

-   -   Cy¹ is phenyl, which is optionally substituted with 1, 2, 3, or        4 independently selected R¹¹ substituents;    -   R¹² is phenyl, which is optionally substituted with 1, 2, 3, or        4 independently selected R^(12A) substituents;    -   each R¹¹ is independently selected from halo, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; and    -   each R^(12A) is independently selected from halo, C₁₋₆ alkyl,        C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments:

-   -   Cy¹ is phenyl, which is optionally substituted with 1 or 2        independently selected R¹¹ substituents;    -   R¹² is phenyl, which is optionally substituted with 1 or 2        independently selected R^(12A) substituents;    -   each R¹¹ is independently selected from halo, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; and    -   each R^(12A) is independently selected from halo, C₁₋₆ alkyl,        C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments:

-   -   Cy¹ is phenyl, which is optionally substituted with 1, 2, 3, or        4 independently selected R¹¹ substituents;    -   R¹² is phenyl, which is optionally substituted with 1, 2, 3, or        4 independently selected R^(12A) substituents;    -   each R¹¹ is independently selected from halo; and    -   each R^(12A) is independently selected from halo.

In some embodiments:

-   -   Cy¹ is phenyl, which is optionally substituted with 1 or 2        independently selected R¹¹ substituents;    -   R¹² is phenyl, which is optionally substituted with 1 or 2        independently selected R^(12A) substituents;    -   each R¹¹ is independently selected from halo; and    -   each R^(12A) is independently selected from halo.

In some embodiments:

-   -   Cy¹ is phenyl, which is optionally substituted with 1 or 2        independently selected R¹¹ substituents;    -   R¹² is phenyl, which is optionally substituted with 1 or 2        independently selected R^(12A) substituents;    -   each R¹¹ is fluoro; and    -   each R^(12A) is fluoro.

In some embodiments, Cy¹ and R¹² are each fluorophenyl.

In some embodiments:

-   -   W is CR⁷, C(O), N, or NR⁷;    -   X is CR⁸, C(O), N, or NR⁸;    -   Y is CH;    -   Z is CH;    -   n is 0, 1, or 2;    -   each R² is independently selected from halo, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl,        5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN, NO₂,        OR^(a2), NHOR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),        C(O)NR^(c2)(OR^(a2)), C(O)OR^(d2), OC(O)R^(b2),        OC(O)NR^(c2)R^(d2), NR^(c2), NR^(c2)NR^(c2)R^(d2),        NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2),        C(═NR^(c2))R^(b2), C(═NR^(c2))NR^(c2)R^(d2),        NR^(c2)C(═NR²)NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))R^(b2),        NR^(c2)S(O)R^(b2) NR^(c2)S(O)NR^(c2)R^(d2), NR^(c2)S(O)₂R^(b2),        NR^(c2)S(O)(═NR^(e2))R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),        S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), S(O)₂NR^(c2)R^(d2),        OS(O)(═NR^(e2))R^(b2), and OS(O)₂R^(b2);    -   each R^(a2), R^(c2), and R^(d2) is independently selected from        H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 membered        heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆        alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 membered        heterocycloalkyl)-C₁₋₆ alkyl-;    -   or, any R^(c2) and R^(d2) attached to the same N atom, together        with the N atom to which they are attached, form a 5-6 membered        heteroaryl or a 4-7 membered heterocycloalkyl group;    -   each R^(b2) is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl,        5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,        phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-7 membered        heterocycloalkyl)-C₁₋₆ alkyl-;    -   each R^(e2) is independently selected from H, OH, CN, C₁₋₆        alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆        alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered        heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,        C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆        alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-;    -   R³ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered        heteroaryl, and 4-7 membered heterocycloalkyl-, wherein the C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6        membered heteroaryl, and 4-7 membered heterocycloalkyl of R³ are        each optionally substituted with 1, 2, 3, or 4 independently        selected R^(M) substituents;    -   R⁵ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered        heteroaryl, 4-7 membered heterocycloalkyl, wherein the C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6        membered heteroaryl, and 4-7 membered heterocycloalkyl of R⁵ are        each optionally substituted with 1, 2, 3, or 4 independently        selected R^(M) substituents;    -   R⁷ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, and C₂₋₆ alkynyl;    -   R⁸ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, —C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆        alkyl-, CN, NO₂, OR^(a8), SR^(a8), NHOR^(a8), C(O)R^(b8),        C(O)NR^(c8)R^(d8), C(O)NR^(c8)(OR^(a8)), C(O)OR^(a8),        OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8),        NR^(c8)NR^(c8)R^(d8), NR^(c8)C(O)R^(b8), NR^(c8)C(O)OR^(a8),        NR^(c8)C(O)NR^(c8)R^(d8), C(═NR^(e8))R^(b8),        C(═NR^(e8))NR^(c8)R^(d8), C(═NOR^(e8))R^(b8),        C(═NOR^(e8))OR^(a8), NR^(c8)C(═NR^(e8))NR^(c8)R^(d8),        NR^(c8)C(═NR^(e8))R^(b8), NR^(c8)S(O)R^(b8),        NR^(c8)S(O)NR^(c8)R^(d8), NR^(c8)S(O)₂R^(b8),        NR^(c8)S(O)(═NR^(e8))R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8),        S(O)R^(b8), S(O)NR^(c8)R^(d8), S(O)₂R^(b8), S(O)₂NR^(c8)R^(d8),        OS(O)(═NR^(e8))R^(b8), and OS(O)₂R^(b8), wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl- of R⁸ are each optionally        substituted with 1, 2, 3, or 4 independently selected R^(8A)        substituents;    -   each R^(a8), R^(c8), and R^(d8) is independently selected from        H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀        aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl- of R^(a8), R^(c8) and R^(d8) are        each optionally substituted with 1, 2, 3, or 4 independently        selected R^(8A) substituents;    -   or, any R^(c8) and R^(d8) attached to the same N atom, together        with the N atom to which they are attached, form a 5-10 membered        heteroaryl or a 4-10 membered heterocycloalkyl group, wherein        the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl        group is optionally substituted with 1, 2, 3, or 4 independently        selected R^(8A) substituents;    -   each R^(b8) is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl- of R^(b8) are each optionally        substituted with 1, 2, 3, or 4 independently selected R^(8A)        substituents;    -   each R^(e8) is independently selected from H, OH, CN, C₁₋₆        alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-;    -   each R^(8A) is independently selected from halo, oxo, C₁₋₆        alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,        C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a81), SR^(a81),        NHOR^(a81), C(O)R^(b81), C(O)NR^(c81)R^(d81),        C(O)NR^(c81)(OR^(a81)), C(O)OR^(a81), OC(O)R^(b81),        OC(O)NR^(c81)R^(d81), NR^(c81)R^(d81), NR^(c81)NR^(c81)R^(d81),        NR^(c81)C(O)R^(b8), NR^(c81)C(O)OR, NR^(c81)C(O)NR^(c81)R^(d81),        C(═NR^(e81))R^(b81), C(═NR^(c81))NR^(c81)R^(d81),        C(═NOR^(e81))R^(b81), C(═NOR^(a81))OR^(a81),        NR^(c81)C(═NR^(e81))NR^(c81)R^(d81),        NR^(c81)C(═NR^(e81))R^(b81), NR^(c81)S(O)R^(b1),        NR^(c81)S(O)NR^(c81)R^(d81), NR^(c81)S(O)₂R^(b81),        NR^(c81)S(O)(═NR^(e81))R^(b81), NR^(c81)S(O)₂NR^(c81)R^(d81),        S(O)R^(b81), S(O)NR^(c81)R^(d81), S(O)₂R^(b81),        S(O)₂NR^(c81)R^(d81), OS(O)(═NR^(e81))R^(b81), and        OS(O)₂R^(b81), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,        and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(8A) are        each optionally substituted with 1, 2, 3, or 4 independently        selected R^(M) substituents;    -   each R^(a81), R^(c81), and R^(d81) is independently selected        from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,        C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆        alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,        wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,        C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a81), R^(c81) and        R^(d81) are each optionally substituted with 1, 2, 3, or 4        independently selected R^(M) substituents;    -   or, any R^(c81) and R^(d81) attached to the same N atom,        together with the N atom to which they are attached, form a 5-10        membered heteroaryl or a 4-10 membered heterocycloalkyl group,        wherein the 5-10 membered heteroaryl or 4-10 membered        heterocycloalkyl group is optionally substituted with 1, 2, 3,        or 4 independently selected R^(M) substituents;    -   each R^(b81) is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl- of R^(b81) are each optionally        substituted with 1, 2, 3, or 4 independently selected R^(M)        substituents;    -   each R^(e81) is independently selected from H, OH, CN, C₁₋₆        alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-;    -   L¹ is C₁₋₃ alkyl;    -   Cy¹ is phenyl or 5-6 membered heteroaryl, wherein the phenyl or        5-6 membered heteroaryl are each optionally substituted with 1,        2, 3, or 4 independently selected R¹¹ substituents;    -   each R¹¹ is independently selected from halo, oxo, C₁₋₆ alkyl,        C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a11), SR^(a11),        NHOR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11),        C(O)NR^(c11)(OR^(a11)), C(O)OR^(a11), OC(O)R^(b11),        OC(O)NR^(c11)R^(d11), NR^(c11)R^(c11)R^(d11),        NR^(c11)NR^(c11)NR^(d11), NR^(c11)C(O)R^(b11),        NR^(c11)C(O)OR^(a11), NR^(c11)C(O)NR^(c11)R^(d11),        C(═NR^(e11))R^(b11), C(═NR^(e11))NR^(c11)R^(d11),        NR^(c11)C(═NR^(e11))NR^(c11)R^(d11),        NR^(c11)C(═NR^(e11))R^(b11), NR^(c11)S(O)R^(b11),        NR^(c11)S(O)NR^(c11)R^(d11), NR^(c11)S(O)₂R^(b11),        NR^(c11)S(O)(═NR^(e11))R^(b11), NR^(c11)S(O)₂NR^(c11)R^(d11),        S(O)R^(b11), S(O)NR^(c11)R^(d11), S(O)₂R^(b11),        S(O)₂NR^(c11)R^(d11), OS(O)(═NR^(e11))R^(b11), and        OS(O)₂R^(b11), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,        and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R¹¹ are each        optionally substituted with 1, 2, 3, or 4 independently selected        R^(11A) substituents;    -   each R^(a11), R^(c11), and R^(d11) is independently selected        from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,        and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a11), R^(c11) and        R^(d11) are each optionally substituted with 1, 2, 3, or 4        independently selected R^(11A) substituents;    -   or, any R^(c11) and R^(d11) attached to the same N atom,        together with the N atom to which they are attached, form a 5-10        membered heteroaryl or a 4-10 membered heterocycloalkyl group,        wherein the 5-10 membered heteroaryl or 4-10 membered        heterocycloalkyl group is optionally substituted with 1, 2, 3,        or 4 independently selected R^(11A) substituents;    -   each R^(b11) is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl- of R^(b11) are each optionally        substituted with 1, 2, 3, or 4 independently selected R^(11A)        substituents;    -   each R^(e11) is independently selected from H, OH, CN, C₁₋₆        alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-;    -   each R^(11A) is independently selected from halo, C₁₋₆ alkyl,        C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇        cycloalkyl, 5-6 membered heteroaryl, 4-7 membered        heterocycloalkyl, CN, NO₂, OR^(a111), C(O)NR^(c111)R^(d111),        C(O)OR^(a111), NR^(c111)R^(d111), S(O)NR^(c111)R^(d111),        S(O)₂R^(b111), S(O)₂NR^(c111)R^(d111), and OS(O)₂R^(b111),        wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇        cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered        heterocycloalkyl of R^(11A) are each optionally substituted with        1, 2, 3, or 4 independently selected R^(M) substituents;    -   each R^(a111), R^(c111), and R^(d111) is independently selected        from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 membered        heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆        alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 membered        heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered        heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,        C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆        alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl- of        R^(a111), R^(c111) and R^(d111) are each optionally substituted        with 1, 2, 3, or 4 independently selected R^(M) substituents;    -   or, any R^(c111) and R^(d111) attached to the same N atom,        together with the N atom to which they are attached, form a 5-6        membered heteroaryl or a 4-7 membered heterocycloalkyl group,        wherein the 5-6 membered heteroaryl or 4-7 membered        heterocycloalkyl group is optionally substituted with 1, 2, 3,        or 4 independently selected R^(M) substituents;    -   each R^(b111) is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl,        5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,        phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-7 membered        heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered        heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,        C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆        alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl- of        R^(b111) are each optionally substituted with 1, 2, 3, or 4        independently selected R^(M) substituents;    -   R¹² is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆        alkyl-, CN, NO₂, OR^(a12), SR^(a12), NHOR^(a12), C(O)R^(b12),        C(O)NR^(c12)R^(d12), C(O)NR^(c12)(OR^(a12)), C(O)OR^(a12),        OC(O)R^(b12), OC(O)NR^(c12)R^(d12), NR^(c12)R^(d12),        NR^(c12)NR^(c12)R^(d12), NR^(c12)C(O)R^(b12),        NR^(c12)C(O)OR^(a12), NR^(c12)C(O)NR^(c12)R^(d12),        C(═NR^(e12))R^(b12), C(═NR^(e12))NR^(c12)R^(d12),        NR^(c12)C(═NR^(e12))NR^(c12)NR^(d12),        NR^(c12)C(═NR^(e12))R^(b12), NR^(c12)S(O)R^(b12),        NR^(c12)S(O)NR^(c12)R^(d12), NR^(c12)S(O)₂R^(b12),        NR^(c12)S(O)(═NR^(e12))R^(b12), NR^(c12)S(O)₂NR^(c12)R^(d12),        S(O)R^(b12), S(O)NR^(c12)R^(d12), S(O)₂R^(b12),        S(O)₂NR^(c12)R^(d12), OS(O)(═NR^(e12))R^(b12), and        OS(O)₂R^(b12), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,        C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆        alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R²        are each optionally substituted with 1, 2, 3, or 4 independently        selected R^(12A) substituents;    -   each R^(a12), R^(c12), and R^(d12) is independently selected        from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,        C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆        alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,        wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,        C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a12), R^(c12) and        R^(d12) are each optionally substituted with 1, 2, 3, or 4        independently selected R^(12A) substituents;    -   or, any R^(c12) and R^(d12) attached to the same N atom,        together with the N atom to which they are attached, form a 5-10        membered heteroaryl or a 4-10 membered heterocycloalkyl group,        wherein the 5-10 membered heteroaryl or 4-10 membered        heterocycloalkyl group is optionally substituted with 1, 2, 3,        or 4 independently selected R^(12A) substituents;    -   each R^(b12) is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl- of R² are each optionally        substituted with 1, 2, 3, or 4 independently selected R^(12A)        substituents;    -   each R^(e12) is independently selected from H, OH, CN, C₁₋₆        alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-;    -   each R^(12A) is independently selected from halo, C₁₋₆ alkyl,        C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a121), SR^(a121),        NHOR^(a121), C(O)R^(b121), C(O)NR^(c121)R^(d121),        C(O)NR^(c121)(OR^(a121)), C(O)OR^(a121), OC(O)R^(b121),        OC(O)NR^(b121), OC(O)NR^(c121)R^(d121), NR^(c121)R^(d121),        NR^(c121)NR^(c121)R^(d121), NR^(c121)C(O)R^(b121),        NR^(c121)C(o)OR^(a121), NR^(c121)C(O)NR^(c121)R^(d121),        C(═NR^(e121))R^(b21), C(═NR^(e121))NR^(c121)R^(d121),        NR^(c121)C(═NR^(e121))NR^(c121)R^(d121),        NR^(c121)C(═NR^(e121))R^(b121), NR^(c121)S(O)R^(b121),        NR^(c121)S(O)NR^(c121)R^(d121), NR^(c121)S(O)₂R^(b121),        NR^(c121)S(O)(═NR^(e121))R^(b121)        NR^(c121)S(O)₂NR^(c121)R^(d121), S(O)R^(b121),        S(O)NR^(c121)R^(d121), S(O)₂R^(b121), S(O)₂NR^(c121)R^(d121),        OS(O)(═NR^(e121))R^(b121), and OS(O)₂R^(b121);    -   each R^(a121), R^(c121), and R^(d121) is independently selected        from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,        and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-;    -   or, any R^(c121) and R^(d121) attached to the same N atom,        together with the N atom to which they are attached, form a 5-10        membered heteroaryl or a 4-10 membered heterocycloalkyl group;    -   each R^(b121) is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl-;    -   each R^(e121) is independently selected from H, OH, CN, C₁₋₆        alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-; and    -   each R^(M) is independently selected from H, OH, halo, oxo, CN,        C(O)OH, NH₂, NO₂, SF₅, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,        C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇        cycloalkyl, 5-6 membered heteroaryl, 4-7 membered        heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆        alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 membered        heterocycloalkyl)-C₁₋₆ alkyl-.

In some embodiments:

-   -   W is CR⁷, N, or NR⁷;    -   X is CR⁸ or C(O);    -   Y is CH;    -   Z is CH;    -   n is 0, 1, or 2;    -   each R² is independently selected from halo, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;    -   R³ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, and C₂₋₆ alkynyl;    -   R⁵ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, and C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,        and C₂₋₆ alkynyl of R⁵ are each optionally substituted with 1,        2, 3, or 4 independently selected R^(M) substituents;    -   R⁷ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, and C₂₋₆ alkynyl;    -   R⁸ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, —C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆        alkyl-, CN, and OR⁸, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl), 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl- of R⁸ are each optionally        substituted with 1, 2, 3, or 4 independently selected R^(8A)        substituents;    -   each R^(a8) is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;    -   each R^(8A) is independently selected from halo, C₁₋₆ alkyl,        C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and CN;    -   L¹ is C₁₋₃ alkyl;    -   Cy¹ is phenyl or 5-6 membered heteroaryl, wherein the phenyl or        5-6 membered heteroaryl are each optionally substituted with 1,        2, 3, or 4 independently selected R¹¹ substituents;    -   each R¹¹ is independently selected from halo, oxo, C₁₋₆ alkyl,        C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a11), SR^(a11),        NHOR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11),        C(O)NR^(c11)(OR^(a11)), C(O)OR^(a11), OC(O)R^(b11),        OC(O)NR^(c11)R^(d11), NR^(c11)R^(d11), NR^(c11)NR^(c11)R^(d11),        NR^(c11)C(O)R^(b11), NR^(c11)C(O)OR^(a11),        NR^(c11)C(O)NR^(c11)R^(d11), C(═NR^(e11))R^(b11),        C(═NR^(e11))NR^(c11)R^(d11),        NR^(c11)C(═NR^(e11))NR^(c11)R^(d11),        NR^(c11)C(═NR^(e11))R^(b11), NR^(c11)S(O)R^(b11),        NR^(c11)S(O)NR^(c11)R^(d11), NR^(c11)S(O)₂R^(b11),        NR^(c11)S(O)(═NR^(e11))R^(b11), NR^(c11)S(O)₂NR^(c11)R^(d11),        S(O)R^(b11), S(O)NR^(c11)R^(d11), S(O)₂R^(b11),        S(O)₂NR^(c11)R^(d11), OS(O)(═NR^(e11))R^(b11), and        OS(O)₂R^(b11), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,        and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R¹ are each        optionally substituted with 1, 2, 3, or 4 independently selected        R^(11A) substituents;    -   each R^(a11), R^(c11), and R^(d11) is independently selected        from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,        and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a11), R^(c11) and        R^(d11) are each optionally substituted with 1, 2, 3, or 4        independently selected R^(11A) substituents;    -   or, any R^(c11) and R^(d11) attached to the same N atom,        together with the N atom to which they are attached, form a 5-10        membered heteroaryl or a 4-10 membered heterocycloalkyl group,        wherein the 5-10 membered heteroaryl or 4-10 membered        heterocycloalkyl group is optionally substituted with 1, 2, 3,        or 4 independently selected R^(11A) substituents;    -   each R^(b11) is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl- of R^(b11) are each optionally        substituted with 1, 2, 3, or 4 independently selected R^(11A)        substituents;    -   each R^(e11) is independently selected from H, OH, CN, C₁₋₆        alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-;    -   each R^(11A) is independently selected from halo, C₁₋₆ alkyl,        C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇        cycloalkyl, 5-6 membered heteroaryl, 4-7 membered        heterocycloalkyl, CN, NO₂, OR^(a111), C(O)NR^(c111)R^(d111),        C(O)OR^(a111), NR^(c111)R^(d111), S(O)NR^(c111)R^(d111),        S(O)₂R^(b111), S(O)₂NR^(c111)R^(d111), and OS(O)₂R^(b111),        wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇        cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered        heterocycloalkyl of R^(11A) are each optionally substituted with        1, 2, 3, or 4 independently selected R^(M) substituents;    -   each R^(a111), R^(c111), and R^(d111) is independently selected        from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 membered        heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆        alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 membered        heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered        heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,        C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆        alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl- of        R^(a111), R^(c111) and R^(d111) are each optionally substituted        with 1, 2, 3, or 4 independently selected R^(M) substituents;    -   or, any R^(c111) and R^(d111) attached to the same N atom,        together with the N atom to which they are attached, form a 5-6        membered heteroaryl or a 4-7 membered heterocycloalkyl group,        wherein the 5-6 membered heteroaryl or 4-7 membered        heterocycloalkyl group is optionally substituted with 1, 2, 3,        or 4 independently selected R^(M) substituents;    -   each R^(b111) is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl,        5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,        phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-7 membered        heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered        heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,        C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆        alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl- of        R^(b111) are each optionally substituted with 1, 2, 3, or 4        independently selected R^(M) substituents;    -   R¹² is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆        alkyl-, CN, NO₂, OR^(a12), SR^(a12), NHOR^(a12), C(O)R^(b12),        C(O)NR^(c12)R^(d12), C(O)NR^(c12)(OR^(a12)), C(O)OR^(a12),        OC(O)R^(b12), OC(O)NR^(c12)R^(d12), NR^(c12)R^(d12),        NR^(c12)NR^(c12)R^(d12), NR^(c12)C(O)R^(b12),        NR^(c12)C(O)OR^(a12), NR^(c12)C(O)NR^(c12)R^(d12),        C(═NR^(e12))R^(b12), C(═NR^(e12))NR^(c12)R^(d12),        NR^(c12)C(═NR^(e12))NR^(c12)R^(d12),        NR^(c12)C(═NR^(e12))R^(b12), NR^(c12)S(O)R^(b12),        NR^(c12)S(O)NR^(c12)R^(d12), NR^(c12)S(O)₂R^(b12),        NR^(c12)S(O)(═NR^(e12))R^(b12), NR^(c12)S(O)₂NR^(c12)R^(d12),        S(O)R^(b12), S(O)NR^(c12)R^(d12), S(O)₂R^(b12),        S(O)₂NR^(c12)R^(d12), OS(O)(═NR^(e12))R^(b12), and        OS(O)₂R^(b12), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,        and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R² are each        optionally substituted with 1, 2, 3, or 4 independently selected        R^(12A) substituents;    -   each R^(a12), R^(c12), and R^(d12) is independently selected        from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,        C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆        alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,        wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,        C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a12), R^(c12) and        R^(d12) are each optionally substituted with 1, 2, 3, or 4        independently selected R^(12A) substituents;    -   or, any R^(c12) and R^(d12) attached to the same N atom,        together with the N atom to which they are attached, form a 5-10        membered heteroaryl or a 4-10 membered heterocycloalkyl group,        wherein the 5-10 membered heteroaryl or 4-10 membered        heterocycloalkyl group is optionally substituted with 1, 2, 3,        or 4 independently selected R^(12A) substituents;    -   each R^(b12) is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl- of R² are each optionally        substituted with 1, 2, 3, or 4 independently selected R^(12A)        substituents;    -   each R^(e12) is independently selected from H, OH, CN, C₁₋₆        alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-;    -   each R^(12A) is independently selected from halo, C₁₋₆ alkyl,        C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a121), SR^(a121),        NHOR^(a121), C(O)R^(b121), C(O)NR^(c121)R^(d121),        C(O)NR^(c121)(OR^(a121)), C(O)OR^(a121), OC(O)R^(b121),        OC(O)NR^(c121)R^(d121), NR^(c121)R^(c121)R^(d121),        NR^(c122)R^(c121)R^(d121), NR^(c121)C(O)R^(b121),        NR^(c121)C(o)OR^(a121), NR^(c121)C(O)NR^(c121)R^(d121),        C(═NR^(e121))R^(b21), C(═NR^(e121))NR^(c121)R^(d121),        NR^(c121)C(═NR^(c121))NR^(c121)R^(d121),        NR^(c121)C(═NR^(e121))R^(b121), NR^(c121)S(O)R^(b121),        NR^(c121)S(O)NR^(c121)R^(d121), NR^(c121)S(O)₂R^(b121),        NR^(c121)S(O)(═NR^(e121))R^(b121),        NR^(c121)S(O)₂NR^(c121)R^(d121), S(O)R^(b121),        S(O)NR^(c121)R^(d121), S(O)₂R^(b121), S(O)₂NR^(c121)R^(d121),        OS(O)(═NR^(e121))R^(b121), and OS(O)₂R^(b121);    -   each R^(a121), R^(c121), and R^(d121) is independently selected        from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,        C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆        alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-;    -   or, any R^(c121) and R^(d121) attached to the same N atom,        together with the N atom to which they are attached, form a 5-10        membered heteroaryl or a 4-10 membered heterocycloalkyl group;    -   each R^(b121) is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆        alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₆ alkyl-;    -   each R^(e121) is independently selected from H, OH, CN, C₁₋₆        alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered        heteroaryl)-C₁₋₆ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₆ alkyl-; and    -   each R^(M) is independently selected from H, OH, halo, oxo, CN,        C(O)OH, NH₂, NO₂, SF₅, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,        C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇        cycloalkyl, 5-6 membered heteroaryl, 4-7 membered        heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆        alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 membered        heterocycloalkyl)-C₁₋₆ alkyl-.

In some embodiments, the compound of Formula I is a compound of FormulaII:

-   -   or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I is a compound of FormulaIII:

-   -   or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I is a compound of FormulaIV:

-   -   or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I is a compound of FormulaV:

-   -   or a pharmaceutically acceptable salt thereof, wherein m is 0,        1, 2, 3, 4, or 5.

In some embodiments, the compound of Formula I is a compound of FormulaVI:

-   -   or a pharmaceutically acceptable salt thereof, wherein m is 0,        1, 2, 3, 4, or 5.

In some embodiments, the compound of Formula I is a compound of FormulaVII:

-   -   or a pharmaceutically acceptable salt thereof, wherein m is 0,        1, 2, 3, 4, or 5.

In some embodiments, the compound provided herein is selected from:

-   (8aR,11R)-10-(bis(4-fluorophenyl)methyl)-5,7,11-trimethyl-6,8-dioxo-5,7,8,8a,9,10,11,12-octahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-2-carbonitrile;-   (8aR,11R)-10-(bis(4-fluorophenyl)methyl)-7-(2-methoxyethyl)-5,11-dimethyl-6,8-dioxo-5,7,8,8a,9,10,11,12-octahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-2-carbonitrile;-   (2R,4aR)-3-(bis(4-fluorophenyl)methyl)-2,6,8-trimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinoline-5,7-dione;-   (8aR,11R)-10-(bis(4-fluorophenyl)methyl)-2-fluoro-5,7,11-trimethyl-5,7,9,10,11,12-hexahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-6,8(8aH)-dione;-   (8aR,11R)-10-(bis(4-fluorophenyl)methyl)-2,5,7,11-tetramethyl-5,7,9,10,11,12-hexahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-6,8(8aH)-dione;    2-((8aR,11R)-10-(bis(4-fluorophenyl)methyl)-5,7,11-trimethyl-6,8-dioxo-5,7,8,8a,9,10,11,12-octahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridin-2-yl)acetonitrile;-   (8aR,11R)-10-(bis(4-fluorophenyl)methyl)-2-methoxy-5,7,11-trimethyl-5,7,9,10,11,12-hexahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-6,8(8aH)-dione;-   (8aR,11R)-10-(bis(4-fluorophenyl)methyl)-5,7,11-trimethyl-2-(1-methyl-1H-pyrazol-4-yl)-5,7,9,10,11,12-hexahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-6,8(8aH)-dione;    and-   (8aR,11R)-10-(bis(4-fluorophenyl)methyl)-5,7,11-trimethyl-5,7,9,10,11,12-hexahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-2,6,8(8aH)-trione;    or a pharmaceutically acceptable salt thereof.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

At various places in the present specification, divalent linkingsubstituents are described. It is specifically intended that eachdivalent linking substituent include both the forward and backward formsof the linking substituent. For example, —NR(CR′R″)_(n)-includes both—NR(CR′R″)_(n)— and —(CR′R″)_(n)NR—. Where the structure clearlyrequires a linking group, the Markush variables listed for that groupare understood to be linking groups.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted. The substituents are independently selected, andsubstitution may be at any chemically accessible position. As usedherein, the term “substituted” means that a hydrogen atom is removed andreplaced by a substituent. A single divalent substituent, e.g., oxo, canreplace two hydrogen atoms. It is to be understood that substitution ata given atom is limited by valency.

As used herein, the phrase “each ‘variable’ is independently selectedfrom” means substantially the same as wherein “at each occurrence‘variable’ is selected from.”

Throughout the definitions, the terms “C_(n-m)” and “C_(m-n)” indicatesa range which includes the endpoints, wherein n and m are integers andindicate the number of carbons. Examples include C₁₋₃, C₁₋₄, C₁₋₆, andthe like.

As used herein, the term “C_(n-m) alkyl”, employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having n to m carbons. Examplesof alkyl moieties include, but are not limited to, chemical groups suchas methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (iPr), n-butyl,tert-butyl, isobutyl, sec-butyl; higher homologs such as2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl,and the like. In some embodiments, the alkyl group contains from 1 to 6carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, from 2to 6 carbon atoms, from 2 to 4 carbon atoms, from 2 to 3 carbon atoms,or 1 to 2 carbon atoms.

As used herein, “C_(n-m) alkenyl” refers to an alkyl group having one ormore double carbon-carbon bonds and having n to m carbons. Examplealkenyl groups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments,the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, “C_(n-m) alkynyl” refers to an alkyl group having one ormore triple carbon-carbon bonds and having n to m carbons. Examplealkynyl groups include, but are not limited to, ethynyl, propyn-1-yl,propyn-2-yl, and the like. In some embodiments, the alkynyl moietycontains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkoxy”, employed alone or incombination with other terms, refers to a group of formula —O-alkyl,wherein the alkyl group has n to m carbons. Example alkoxy groupsinclude, but are not limited to, methoxy, ethoxy, propoxy (e.g.,n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), andthe like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1to 3 carbon atoms.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to an aromatic hydrocarbon group, which may bemonocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term“C_(n-m) aryl” refers to an aryl group having from n to m ring carbonatoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl,phenanthrenyl, and the like. In some embodiments, aryl groups have from5 to 10 carbon atoms. In some embodiments, the aryl group is phenyl ornaphthyl. In some embodiments, the aryl is phenyl.

As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, ahalo is F, Cl, or Br. In some embodiments, a halo is F or Cl. In someembodiments, a halo is F. In some embodiments, a halo is Cl.

As used herein, “C_(n-m) haloalkoxy” refers to a group of formula—O-haloalkyl having n to m carbon atoms. Example haloalkoxy groupsinclude OCF₃ and OCHF₂. In some embodiments, the haloalkoxy group isfluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) haloalkyl”, employed alone or incombination with other terms, refers to an alkyl group having from onehalogen atom to 2s+1 halogen atoms which may be the same or different,where “s” is the number of carbon atoms in the alkyl group, wherein thealkyl group has n to m carbon atoms. In some embodiments, the haloalkylgroup is fluorinated only. In some embodiments, the alkyl group has 1 to6, 1 to 4, or 1 to 3 carbon atoms. Example haloalkyl groups include CF₃,C₂F₅, CHF₂, CH₂F, CCl₃, CHCl₂, C₂Cl₅ and the like.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbonsincluding cyclized alkyl and alkenyl groups. Cycloalkyl groups caninclude mono- or polycyclic (e.g., having 2 fused rings) groups,spirocycles, and bridged rings (e.g., a bridged bicycloalkyl group).Ring-forming carbon atoms of a cycloalkyl group can be optionallysubstituted by oxo or sulfido (e.g., C(O) or C(S)). Also included in thedefinition of cycloalkyl are moieties that have one or more aromaticrings fused (i.e., having a bond in common with) to the cycloalkyl ring,for example, benzo or thienyl derivatives of cyclopentane, cyclohexane,and the like. A cycloalkyl group containing a fused aromatic ring can beattached through any ring-forming atom including a ring-forming atom ofthe fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9,or 10 ring-forming carbons (i.e., C₃₋₁₀). In some embodiments, thecycloalkyl is a C₃₋₁₀ monocyclic or bicyclic cycloalkyl. In someembodiments, the cycloalkyl is a C₃₋₇ monocyclic cycloalkyl.

In some embodiments, the cycloalkyl is a C₄₋₇ monocyclic cycloalkyl. Insome embodiments, the cycloalkyl is a C₄₋₁₀ spirocycle or bridgedcycloalkyl (e.g., a bridged bicycloalkyl group). Example cycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, cubane, adamantane,bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptanyl,bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, andthe like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

As used herein, “heteroaryl” refers to a monocyclic or polycyclic (e.g.,having 2 fused rings) aromatic heterocycle having at least oneheteroatom ring member selected from N, O, S and B. In some embodiments,the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring membersindependently selected from N, O, S and B. In some embodiments, anyring-forming N in a heteroaryl moiety can be an N-oxide. In someembodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclicheteroaryl having 1, 2, 3, or 4 heteroatom ring members independentlyselected from N, O, S, and B. In some embodiments, the heteroaryl is a5-, 7-, 8-, 9-, or, 10-membered monocyclic or bicyclic heteroaryl having1, 2, 3, or 4 heteroatom ring members independently selected from N, O,S, and B. In some embodiments, the heteroaryl is a 5-10 memberedmonocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ringmembers independently selected from N, O, and S. In some embodiments,the heteroaryl is a 5-, 7-, 8-, 9-, or 10-membered monocyclic orbicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring membersindependently selected from N, O, and S. In some embodiments, theheteroaryl is a 5-6 membered monocyclic heteroaryl having 1 or 2heteroatom ring members independently selected from N, O, S, and B. Insome embodiments, the heteroaryl is a 5 membered monocyclic heteroarylhaving 1 or 2 heteroatom ring members independently selected from N, O,S, and B. In some embodiments, the heteroaryl is a 5 membered monocyclicheteroaryl having 1 or 2 heteroatom ring members independently selectedfrom N, O, and S. In some embodiments, the heteroaryl group contains 5to 10, 5 to 7, 3 to 7, or 5 to 6 ring-forming atoms. In someembodiments, the heteroaryl group has 1 to 4 ring-forming heteroatoms, 1to 3 ring-forming heteroatoms, 1 to 2 ring-forming heteroatoms or 1ring-forming heteroatom. When the heteroaryl group contains more thanone heteroatom ring member, the heteroatoms may be the same ordifferent. Example heteroaryl groups include, but are not limited to,thienyl (or thiophenyl), furyl (or furanyl), pyrrolyl, imidazolyl,thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl,1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl,1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2-dihydro-1,2-azaborine,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, azolyl, triazolyl,thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzothiophenyl,benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl,triazinyl, thieno[3,2-b]pyridinyl, imidazo[1,2-a]pyridinyl,1,5-naphthyridinyl, 1H-pyrazolo[4,3-b]pyridinyl,triazolo[4,3-a]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl,1H-pyrrolo[2,3-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, indazolyl, and thelike.

As used herein, “heterocycloalkyl” refers to monocyclic or polycyclicheterocycles having at least one non-aromatic ring (saturated orpartially unsaturated ring), wherein one or more of the ring-formingcarbon atoms of the heterocycloalkyl is replaced by a heteroatomselected from N, O, S, and B, and wherein the ring-forming carbon atomsand heteroatoms of a heterocycloalkyl group can be optionallysubstituted by one or more oxo or sulfido (e.g., C(O), S(O), C(S), orS(O)₂, etc.). When a ring-forming carbon atom or heteroatom of aheterocycloalkyl group is optionally substituted by one or more oxo orsulfide, the O or S of said group is in addition to the number ofring-forming atoms specified herein (e.g., a1-methyl-6-oxo-1,6-dihydropyridazin-3-yl is a 6-memberedheterocycloalkyl group, wherein a ring-forming carbon atom issubstituted with an oxo group, and wherein the 6-memberedheterocycloalkyl group is further substituted with a methyl group).Heterocycloalkyl groups include monocyclic and polycyclic (e.g., having2 fused rings) systems. Included in heterocycloalkyl are monocyclic andpolycyclic 3 to 10, 4 to 10, 5 to 10, 4 to 7, 5 to 7, or 5 to 6 memberedheterocycloalkyl groups. Heterocycloalkyl groups can also includespirocycles and bridged rings (e.g., a 5 to 10 membered bridgedbiheterocycloalkyl ring having one or more of the ring-forming carbonatoms replaced by a heteroatom independently selected from N, O, S, andB). The heterocycloalkyl group can be attached through a ring-formingcarbon atom or a ring-forming heteroatom. In some embodiments, theheterocycloalkyl group contains 0 to 3 double bonds. In someembodiments, the heterocycloalkyl group contains 0 to 2 double bonds.

Also included in the definition of heterocycloalkyl are moieties thathave one or more aromatic rings fused (i.e., having a bond in commonwith) to the non-aromatic heterocyclic ring, for example, benzo orthienyl derivatives of piperidine, morpholine, azepine, etc. Aheterocycloalkyl group containing a fused aromatic ring can be attachedthrough any ring-forming atom including a ring-forming atom of the fusedaromatic ring.

In some embodiments, the heterocycloalkyl group contains 3 to 10ring-forming atoms, 4 to 10 ring-forming atoms, 4 to 8 ring-formingatoms, 3 to 7 ring-forming atoms, or 5 to 6 ring-forming atoms. In someembodiments, the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3heteroatoms, 1 to 2 heteroatoms or 1 heteroatom. In some embodiments,the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkylhaving 1 or 2 heteroatoms independently selected from N, O, S and B andhaving one or more oxidized ring members. In some embodiments, theheterocycloalkyl is a monocyclic or bicyclic 5-10, memberedheterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selectedfrom N, O, S, and B and having one or more oxidized ring members. Insome embodiments, the heterocycloalkyl is a monocyclic or bicyclic 5 to10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatomsindependently selected from N, O, and S and having one or more oxidizedring members. In some embodiments, the heterocycloalkyl is a monocyclic5 to 6 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatomsindependently selected from N, O, and S and having one or more oxidizedring members.

Example heterocycloalkyl groups include pyrrolidin-2-one (or2-oxopyrrolidinyl), 1,3-isoxazolidin-2-one, pyranyl, tetrahydropyran,oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl,tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl,isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl,thiazolidinyl, imidazolidinyl, azepanyl, 1,2,3,4-tetrahydroisoquinoline,tetrahydrothiopheneyl, tetrahydrothiopheneyl 1,1-dioxide, benzazapene,azabicyclo[3.1.0]hexanyl, diazabicyclo[3.1.0]hexanyl,oxobicyclo[2.1.1]hexanyl, azabicyclo[2.2.1]heptanyl,diazabicyclo[2.2.1]heptanyl, azabicyclo[3.1.1]heptanyl,diazabicyclo[3.1.1]heptanyl, azabicyclo[3.2.1]octanyl,diazabicyclo[3.2.1]octanyl, oxobicyclo[2.2.2]octanyl,azabicyclo[2.2.2]octanyl, azaadamantanyl, diazaadamantanyl,oxo-adamantanyl, azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl,diazaspiro[3.3]heptanyl, azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl,oxo-azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl, diazaspiro[3.4]octanyl,oxo-azaspiro[3.4]octanyl, azaspiro[2.5]octanyl, diazaspiro[2.5]octanyl,azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, oxo-azaspiro[4.4]nonanyl,azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, diazaspiro[4.4]nonanyl,oxo-diazaspiro[4.4]nonanyl, oxo-dihydropyridazinyl,oxo-2,6-diazaspiro[3.4]octanyl, oxo-pyrrolidinyl, oxo-pyridinyl, and thelike.

As used herein, “C_(o-p) cycloalkyl-C_(n-m) alkyl-” refers to a group offormula cycloalkyl-alkylene-, wherein the cycloalkyl has o to p carbonatoms and the alkylene linking group has n to m carbon atoms.

As used herein “C_(o-p) aryl-C_(n-m) alkyl-” refers to a group offormula aryl-alkylene-, wherein the aryl has o to p carbon atoms and thealkylene linking group has n to m carbon atoms.

As used herein, “heteroaryl-C_(n-m) alkyl-” refers to a group of formulaheteroaryl-alkylene-, wherein alkylene linking group has n to m carbonatoms.

As used herein “heterocycloalkyl-C_(n-m) alkyl-” refers to a group offormula heterocycloalkyl-alkylene-, wherein alkylene linking group has nto m carbon atoms.

As used herein, an “alkyl linking group” or “alkylene linking group” isa bivalent straight chain or branched alkyl linking group (“alkylenegroup”). For example, “C_(o-p) cycloalkyl-C_(n-m) alkyl-”, “C_(o-p)aryl-C_(n-m) alkyl-”, “phenyl-C_(n-m) alkyl-”, “heteroaryl-C_(n-m)alkyl-”, and “heterocycloalkyl-C_(n-m) alkyl-” contain alkyl linkinggroups. Examples of “alkyl linking groups” or “alkylene groups” includemethylene, ethan-1,1-diyl, ethan-1,2-diyl, propan-1,3-dilyl,propan-1,2-diyl, propan-1,1-diyl and the like.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas a pyridin-3-yl ringis attached at the 3-position.

As used herein, the term “oxo” refers to an oxygen atom (i.e., ═O) as adivalent substituent, forming a carbonyl group when attached to a carbon(e.g., C═O or C(O)), or attached to a nitrogen or sulfur heteroatomforming a nitroso, sulfinyl, or sulfonyl group.

As used herein, the term “independently selected from” means that eachoccurrence of a variable or substituent (e.g., each R^(M)), areindependently selected at each occurrence from the applicable list.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent disclosure that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present disclosure are described and may be isolated asa mixture of isomers or as separated isomeric forms. In someembodiments, the compound has the (R)-configuration. In someembodiments, the compound has the (S)-configuration. The Formulas (e.g.,Formula I, Formula IL, etc.) provided herein include stereoisomers ofthe compounds.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallizaion using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asp-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofa-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds provided herein also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone—enol pairs, amide—imidic acidpairs, lactam—lactim pairs, enamine—imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, 2-hydroxypyridine and 2-pyridone, and 1H- and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into oneform by appropriate substitution.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.hydrates and solvates) or can be isolated.

In some embodiments, preparation of compounds can involve the additionof acids or bases to affect, for example, catalysis of a desiredreaction or formation of salt forms such as acid addition salts.

In some embodiments, the compounds provided herein, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds providedherein. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds provided herein, or saltthereof.

The term “compound” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present application also includes pharmaceutically acceptable saltsof the compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present disclosure include the conventionalnon-toxic salts of the parent compound formed, for example, fromnon-toxic inorganic or organic acids. The pharmaceutically acceptablesalts of the present disclosure can be synthesized from the parentcompound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, non-aqueous media like ether, ethylacetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) oracetonitrile (ACN) are preferred. Lists of suitable salts are found inRemington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2(1977), each of which is incorporated herein by reference in itsentirety.

Synthesis

As will be appreciated by those skilled in the art, the compoundsprovided herein, including salts and stereoisomers thereof, can beprepared using known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes. The schemesbelow provide general guidance in connection with preparing thecompounds of the invention. One skilled in the art would understand thatthe preparations shown in the schemes can be modified or optimized usinggeneral knowledge of organic chemistry to prepare various compounds ofthe invention.

Compounds of Formula 1-7 can be synthesized, for example, using theprocess shown in Scheme 1. As depicted in Scheme 1, acylation ofcompounds of Formula 1-1 (e.g., wherein R is an alkyl group, such asmethyl or ethyl) under appropriate conditions (i.e., using aceticanhydride or acetyl chloride in a suitable solvent, such as THF)generates compounds of Formula 1-2. Compounds of Formula 1-1 arecommercially available, or can be readily synthesized according tomethods known by persons skilled in the art. Reaction of compounds ofFormula 1-2 with appropriate electrophiles 1-3 (e.g., methyl iodide)under appropriate conditions (e.g., in the presence of a base, such asCs₂CO₃, in an appropriate solvent, such as N,N-dimethylformamide)affords compounds of Formula 1-4. Cyclization of compounds of Formula1-4 under appropriate conditions (e.g., using a suitable base, such aspotassium bis(trimethylsilyl)amide, in a suitable solvent, such astetrahydrofuran) provides compounds of Formula 1-5. Nitration ofcompounds of Formula 1-5 under suitable conditions (e.g., using HNO₃ ina suitable solvent, such as acetic acid) generates compounds of Formula1-6. Conversion of the hydroxyl group in compounds of Formula 1-6 intoan appropriate leaving group (i.e., wherein LG is triflate or a suitablehalogen) provides compounds of Formula 1-7. For example, compounds ofFormula 1-6 can be reacted with triflic anhydride in an appropriatesolvent, such as CH₂Cl₂, to prepare compounds of Formula 1-7 where LG istriflate (i.e., —OSO₂CF₃). Alternatively, compounds of Formula 1-6 canbe reacted with an appropriate phosphoryl halide (e.g., such as POCl₃)under appropriate conditions (e.g., neat or in an appropriate solvent,such as toluene) to generate compounds of Formula 1-7 where LG is asuitable halogen.

Compounds of Formula I can be prepared, for example, using the processillustrated in Scheme 2. In the process depicted in Scheme 2,nucleophilic aromatic substitution reactions between compounds ofFormula 2-1 (e.g., wherein R is an alkyl group, such as methyl or ethyl)and compounds of Formula 1-7 under appropriate conditions (e.g., in thepresence of a base, such as N,N-diisopropylethylamine, in an appropriatesolvent, such as CH₃CN or 1-butanol) affords compounds of Formula 2-2.Alternatively, compounds of Formula 2-2 can be accessed via suitabletransition metal catalyzed C—N bond forming reactions (e.g., including,but not limited to, Buchwald-Hartwig amination (Chem. Sci. 2011, 2,27-50), Cu-catalyzed amination (Org. React. 2014, 85, 1-688), amongothers) between compounds of Formula 2-1 and compounds of Formula 1-7.Reduction of the nitro group in compounds of Formula 2-2 underappropriate conditions (e.g., iron in the presence of ammonium chloride,or hydrogen gas in the presence of a palladium catalyst, such as Pd/C)followed by intramolecular cyclization provides compounds of Formula2-3. Reaction of compounds of Formula 2-3 with appropriate electrophilesof Formula 2-4 (e.g., methyl iodide) under appropriate conditions (e.g.,in the presence of a base, such as sodium hydride, in a suitablesolvent, such as N,N-dimethylformamide) affords compounds of Formula2-5. Removal of an appropriate protecting group (e.g., wherein PG is agroup such as tert-butoxycarbonyl) from compounds of Formula 2-5 underappropriate conditions (e.g., in the presence of an acid, such as HCl ortrifluoroacetic acid, in a suitable solvent, such as tetrahydrofuran,1-4-dioxane, or CH₂Cl₂) affords compounds of Formula 2-6. Nucleophilicsubstitution reactions of compounds of Formula 2-6 with appropriatelysubstituted compounds of Formula 2-7 under appropriate conditions (e.g.,in the presence of a base, such as N,N-diisopropylethylamine, in anappropriate solvent, such as CH₃CN) generates compounds of Formula I.

The reactions for preparing compounds described herein can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,(e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature). A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

The expressions, “ambient temperature” or “room temperature” or “rt” asused herein, are understood in the art, and refer generally to atemperature, e.g., a reaction temperature, that is about the temperatureof the room in which the reaction is carried out, for example, atemperature from about 20° C. to about 30° C.

Preparation of compounds described herein can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3^(rd) Ed., Wiley &Sons, Inc., New York (1999).

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry, or by chromatographic methods such as high performanceliquid chromatography (HPLC), liquid chromatography-mass spectroscopy(LCMS), or thin layer chromatography (TLC). Compounds can be purified bythose skilled in the art by a variety of methods, including highperformance liquid chromatography (HPLC) and normal phase silicachromatography.

Methods of Use

The compounds described herein can inhibit the activity of DGK.Compounds that inhibit DGK are useful in providing a means of preventingthe growth or inducing apoptosis of cancer cells. Such compounds arealso useful in treating cancer cells exhibiting alterations indiacylglyceraol-regulating enzymes and effectors. It is thereforeanticipated that the compounds of the disclosure are useful in treatingor preventing cancer, such as solid tumors.

In certain embodiments, the disclosure provides a method for treating aDGK-related disorder in a patient in need thereof, comprising the stepof administering to said patient a compound of the disclosure, or apharmaceutically acceptable composition thereof.

The compounds or salts described herein can be selective. By“selective,” it is meant that the compound binds to or inhibits DGKα orDGKζ with greater affinity or potency, respectively, compared to atleast one other DGK isoforms, or kinase, etc. In some embodiments,selectivity can be at least about 2-fold, 5-fold, 10-fold, at leastabout 20-fold, at least about 50-fold, at least about 100-fold, at leastabout 200-fold, at least about 500-fold or at least about 1000-fold. Thecompounds of the present disclosure can also be dual antagonists (i.e.,inhibitors), e.g. inhibit both DGKα and DGKζ kinases. In someembodiments, the compounds of the invention are selective inhibitors ofDGKα (e.g., over one or more other DGK isoforms, or kinase, etc.). Insome embodiments, the compounds of the invention are selectiveinhibitors of DGKζ (e.g., over one or more other DGK isoforms, orkinase, etc.). Selectivity can be measured by methods routine in theart. In some embodiments, selectivity can be tested at the K_(m) ATPconcentration of each enzyme. In some embodiments, the selectivity ofcompounds of the invention can be determined by cellular assaysassociated with particular DGK kinase activity.

Based on compelling evidence that DGKα and DGKζ negatively regulatesignaling pathways downstream of the T cell receptor, developing DGKinhibitors can boost T cell effector function and inhibit tumorprogression. DGK inhibitors can be used to treat, alone or incombination with other therapies, renal cell carcinoma, mesothelioma,glioblastoma multiforme, colorectal cancer, melanoma, pancreatic cancer(Chen, S. S. et al., Front. Cell Dev. Biol., 2016. 4:130; Gu, J. et al.,Oncoimmunol., 2021. 10, e1941566; Jung I.-Y. et al., Cancer Res., 2018.78: p 4692-4703; Sitaram, P., et al., Int. J Mol. Sci., 2019. 20: p5821-5848; Wesley, E. M., et al., Immunohorizons, 2018. 2: p 107-118)

In addition, DGKα has been shown to enhance esophageal squamous cellcarcinoma (ESCC), and human hepatocellular carcinoma (HCC) progression(Chen, J. et al., Oncogene, 2019. 38: p 2533-2550; Takeishi, K. et al.,J. Hepatol., 2012. 57: p 77-83), to support colon and breast cancergrowth in three-dimensional (3D) culture (Torres-Ayuso, P. et al.,Oncotarget, 2014. 5: p 9710-9726), to enhance mammary carcinomainvasiveness (Rainero, E. et al., PLOS ONE, 2014. 9(6): e97144) andpromote metastasis of non-small cell lung cancer (NSCLC) (Fu, L. et al.,Cancer letters, 2022. 532: 215585) whereas DGKζ has been implicated as apotential oncogene in osteosarcoma proliferation (Yu, W. et al., Front.Oncol., 2019. 8:655) and contributed to enhanced invasion of humanmetastatic colon cancer cells (Cai, K. et al., BMC Cancer, 2014.14:208). It has also been reported DGK inhibition has the potential toreduce immunopathology in X-linked lymphoproliferative disease patient(Velnati, S. et al., Eur. J. Med. Chem., 2019. 164: p 378-390; Ruffo, E.et al., Sci. Transl. Med. 2016. 8 (321):321ra7).

In some embodiments, the DGK-related disorder is a solid tumor. Examplesolid tumors include, but are not limited to, breast cancer, colorectalcancer, gastric cancer, and glioblastoma (see e.g., Cooke & Kazanietz,Sci. Signal, 2022, 15, eabo0264:1-26). Example cancers associated withalterations in DAG-regulating enzymes and effector include, but are notlimited to, uveal melanoma, myelodysplastic syndrome (MDS),angiosarcoma, nodal peripheral T cell lymphoma, adult T-cell leukemialymphoma (ATLL), cutaneous T-cell lymphoma (CTCL)/Sezary syndrome,chronic lymphocytic leukemia (CLL), breast cancer, gastric cancer,colorectal cancer, oral squamous cell carcinoma (SCC), esophageal SCC,chronic myeloid leukemia (CML), colon cancer, prostate cancer,hepatocellular carcinoma (HCC), blue nevi, NK/T cell lymphoma, glioma,ovarian cancer, liver cancer, melanoma, heptacarcinoma, ostersarcoma,chordiod glioma, pigmented epithelioid melanocytoma, papillaryglioneuronal tumor, fibrous histiocytoma, pituitary tumor, thyroidcancer, head and neck SCC, lung cancer, pediatric T-cell acutelymphoblastic leukemia (T-ALL), endometrial cancer, angiolipoma,salivary gland cancer, acute myeloid leukemia (AML), Epstein-Barrvirus-associated (EBV)-associated B cell lymphoma, diffuse large B celllymphoma (DLBCL), and cervical cancer (see e.g., Cooke & Kazanietz, Sci.Signal, 2022, 15, eabo0264:1-26).

In some embodiments, the cancer is selected from lung cancer, bladdercancer, urothelial cancer, esophageal cancer, stomach cancer,mesothelioma, liver cancer, diffuse large B cell lymphoma, kidneycancer, head and neck cancer, cholangiocarcinoma, cervical cancer,endocervical cancer, and melanoma.

In some embodiments, the cancer is selected from non-small cell lungcancer (lung squamous cell carcinoma (LUSC), lung adenocarcinoma(LUAD)), bladder urothelial carcinoma, esophageal carcinoma, stomachadenocarcinoma, mesothelioma, liver hepatocellular carcinoma, diffuselarge B cell lymphoma (DLBCL), kidney renal clear cell carcinoma, headand neck squamous cell carcinoma, cholangiocarcinoma, cervical squamouscell carcinoma, endocervical adenocarcinoma, and metastatic melanoma.

In some embodiments, the cancer is a myelodysplastic syndrome. As usedherein, myelodysplastic syndromes are intended to encompassheterogeneous and clonal hematopoietic disorders that are characterizedby ineffective hematopoiesis on one or more of the major myeloid celllineages. Myelodysplastic syndromes are associated with bone marrowfailure, peripheral blood cytopenias, and a propensity to progress toacute myeloid leukemia (AML). Moreover, clonal cytogenetic abnormalitiescan be detected in about 50% of cases with MDS. In 1997, The WorldHealth Organization (WHO) in conjunction with the Society forHematopathology (SH) and the European Association of Hematopathology(EAHP) proposed new classifications for hematopoietic neoplasms (Harris,et al., J Clin Oncol 1999; 17:3835-3849; Vardiman, et al., Blood 2002;100:2292-2302). For MDS, the WHO utilized not only the morphologiccriteria from the French-American-British (FAB) classification but alsoincorporated available genetic, biologic, and clinical characteristicsto define subsets of MDS (Bennett, et al., Br. J. Haematol. 1982;51:189-199). In 2008, the WHO classification of MDS (Table 1) wasfurther refined to allow precise and prognostically relevantsubclassification of unilineage dysplasia by incorporating new clinicaland scientific information (Vardiman, et al., Blood 2009; 114:937-951;Swerdlow, et al., WHO Classification of Tumours of Haematopoietic andLymphoid Tissues. 4th Edition. Lyon France: IARc Press; 2008:88-103;Bunning and Germing, “Myelodysplastic syndromes/neoplasms” in Chapter 5,Swerdlow, et al, eds. WHO Classification of Tumours of Haematopoieticand Lymphoid Tissues. (ed. 4th edition): Lyon, France: IARc Press;2008:88-103).

TABLE 1 2008 WHO Classification for De Novo Myelodysplastic SyndromeSubtype Blood Bone Marrow Refractory cytopenia with Single orBicytopenia Dysplasia in ≥10% of 1 cell unilineage dysplasia (RCUD)line, <5% blasts Refractory anemia with Anemia, no blasts ≥15% oferythroid precursors ring sideroblasts (RARS) w/ring sideroblasts,erythroid dysplasia only, <5% blasts Refractory cytopenia withCytopenia(s), <1 × 10⁹/L Dysplasia in ≥10% of cells in ≥2 multilineagedysplasia monocytes hematopoietic lineages, ±15% ring sideroblasts, <5%blasts Refractory anemia with Cytopenia(s), ≤2% to Unilineage ormultilineage excess blasts-1 (RAEB-1) 4% blasts, <1 × 10⁹/L dysplasia,No Auer rods, 5% to monocytes 9% blasts Refractory anemia withCytopenia(s), ≤5% to Unilineage or multilineage excess blasts-2 (RAEB-2)19% blasts, <1 × 10⁹/L dysplasia, ±Auer rods, 10% to monocytes 19%blasts Myelodysplastic syndrome, Cytopenias Unilineage or no dysplasiabut unclassified (MDS-U) characteristic MDS cytogenetics, <5% blasts MDSassociated with Anemia, platelets Unilineage erythroid. Isolatedisolated del(5q) normal or increased del(5q), <5% blasts

In some embodiments, the myelodysplastic syndrome is refractorycytopenia with unilineage dysplasia (RCUD).

In some embodiments, the myelodysplastic syndrome is refractory anemiawith ring sideroblasts (RARS).

In some embodiments, the myelodysplastic syndrome is refractory anemiawith ring sideroblasts associated with thrombocytosis (RARS-T).

In some embodiments, the myelodysplastic syndrome is refractorycytopenia with multilineage dysplasia.

In some embodiments, the myelodysplastic syndrome is refractory anemiawith excess blasts-1 (RAEB-1).

In some embodiments, the myelodysplastic syndrome is refractory anemiawith excess blasts-2 (RAEB-2).

In some embodiments, the myelodysplastic syndrome is myelodysplasticsyndrome, unclassified (MDS-U).

In some embodiments, the myelodysplastic syndrome is myelodysplasticsyndrome associated with isolated del(5q).

In some embodiments, the myelodysplastic syndrome is refractory toerythropoiesis-stimulating agents.

In some embodiments, the compounds of the disclosure can be useful inthe treatment of myeloproliferative disorder/myelodysplastic overlapsyndrome (MPD/MDS overlap syndrome).

In some embodiments, provided herein is a method of increasing survivalor progression-free survival in a patient, comprising administering acompound provided herein to the patient. In some embodiments, thepatient has cancer. In some embodiments, the patient has a disease ordisorder described herein. As used herein, progression-free survivalrefers to the length of time during and after the treatment of a solidtumor that a patient lives with the disease but it does not get worse.Progression-free survival can refer to the length of time from firstadministering the compound until the earlier of death or progression ofthe disease. Progression of the disease can be defined by RECIST v. 1.1(Response Evaluation Criteria in Solid Tumors), as assessed by anindependent centralized radiological review committee. In someembodiments, administering of the compound results in a progression freesurvival that is greater than about 1 month, about 2 months, about 3months, about 4 months, about 5 months, about 6 months, about 8 months,about 9 months, about 12 months, about 16 months, or about 24 months. Insome embodiments, the administering of the compound results in aprogression free survival that is at least about 1 month, about 2months, about 3 months, about 4 months, about 5 months, about 6 months,about 8 months, about 9 months, or about 12 months; and less than about24 months, about 16 months, about 12 months, about 9 months, about 8months, about 6 months, about 5 months, about 4 months, about 3 months,or about 2 months. In some embodiments, the administering of thecompound results in an increase of progression free survival that is atleast about 1 month, about 2 months, about 3 months, about 4 months,about 5 months, about 6 months, about 8 months, about 9 months, or about12 months; and less than about 24 months, about 16 months, about 12months, about 9 months, about 8 months, about 6 months, about 5 months,about 4 months, about 3 months, or about 2 months.

The present disclosure further provides a compound described herein, ora pharmaceutically acceptable salt thereof, for use in any of themethods described herein.

The present disclosure further provides use of a compound describedherein, or a pharmaceutically acceptable salt thereof, for thepreparation of a medicament for use in any of the methods describedherein.

As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a DGK with a compound described herein includesthe administration of a compound described herein to an individual orpatient, such as a human, having a DGK, as well as, for example,introducing a compound described herein into a sample containing acellular or purified preparation containing the DGK.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent such as an amountof any of the solid forms or salts thereof as disclosed herein thatelicits the biological or medicinal response in a tissue, system,animal, individual or human that is being sought by a researcher,veterinarian, medical doctor or other clinician. An appropriate“effective” amount in any individual case may be determined usingtechniques known to a person skilled in the art.

The phrase “pharmaceutically acceptable” is used herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, immunogenicity or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

As used herein, the phrase “pharmaceutically acceptable carrier orexcipient” refers to a pharmaceutically-acceptable material,composition, or vehicle, such as a liquid or solid filler, diluent,solvent, or encapsulating material. Excipients or carriers are generallysafe, non-toxic and neither biologically nor otherwise undesirable andinclude excipients or carriers that are acceptable for veterinary use aswell as human pharmaceutical use. In one embodiment, each component is“pharmaceutically acceptable” as defined herein. See, e.g., Remington:The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams &Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the AmericanPharmaceutical Association: 2009; Handbook of Pharmaceutical Additives,3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007;Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRCPress LLC: Boca Raton, Fla., 2009.

As used herein, the term “treating” or “treatment” refers to inhibitingthe disease; for example, inhibiting a disease, condition or disorder inan individual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder (i.e., arrestingfurther development of the pathology and/or symptomatology) orameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing the pathology and/or symptomatology) such as decreasing theseverity of disease.

In some embodiments, the compounds of the invention are useful inpreventing or reducing the risk of developing any of the diseasesreferred to herein; e.g., preventing or reducing the risk of developinga disease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease.

It is appreciated that certain features of the disclosure, which are,for clarity, described in the context of separate embodiments, can alsobe provided in combination in a single embodiment (while the embodimentsare intended to be combined as if written in multiply dependent form).Conversely, various features of the disclosure which are, for brevity,described in the context of a single embodiment, can also be providedseparately or in any suitable subcombination.

Combination Therapies I. Immune-Checkpoint Therapies

In some embodiments, DGKα and DGKζ inhibitors provided herein can beused in combination with one or more immune checkpoint inhibitors forthe treatment of cancer as described herein.

Compounds of the present disclosure can be used in combination with oneor more immune checkpoint inhibitors for the treatment of diseases, suchas cancer or infections. Exemplary immune checkpoint inhibitors includeinhibitors against immune checkpoint molecules such as CBL-B, CD20,CD28, CD40, CD70, CD122, CD96, CD73, CD47, CDK2, GITR, CSF1R, JAK, PI3Kdelta, PI3K gamma, TAM, arginase, HPK1, CD137 (also known as 4-1BB),ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, TLR (TLR7/8), TIGIT,CD112R, VISTA, PD-1, PD-L1 and PD-L2. In some embodiments, the immunecheckpoint molecule is a stimulatory checkpoint molecule selected fromCD27, CD28, CD40, ICOS, OX40, GITR and CD137. In some embodiments, theimmune checkpoint molecule is an inhibitory checkpoint molecule selectedfrom A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3,TIGIT, and VISTA. In some embodiments, the compounds provided herein canbe used in combination with one or more agents selected from KIRinhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4inhibitors and TGFR beta inhibitors.

In some embodiments, the compounds provided herein can be used incombination with one or more agonists of immune checkpoint molecules,e.g., OX40, CD27, GITR, and CD137 (also known as 4-1 BB).

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1 or PD-L1, e.g., an anti-PD-1 or anti-PD-L1monoclonal antibody. In some embodiments, the anti-PD-1 or anti-PD-L1antibody is nivolumab, pembrolizumab, atezolizumab, durvalumab,avelumab, cemiplimab, atezolizumab, avelumab, tislelizumab,spartalizumab (PDR001), cetrelimab (JNJ-63723283), toripalimab (JS001),camrelizumab (SHR-1210), sintilimab (IBI308), AB122 (GLS-010), AMP-224,AMP-514/MEDI-0680, BMS936559, JTX-4014, BGB-108, SHR-1210, MEDI4736,FAZ053, BCD-100, KN035, CS1001, BAT1306, LZM009, AK105, HLX10, SHR-1316,CBT-502 (TQB2450), A167 (KL-A167), STI-A101 (ZKAB001), CK-301, BGB-A333,MSB-2311, HLX20, TSR-042, or LY3300054. In some embodiments, theinhibitor of PD-1 or PD-L1 is one disclosed in U.S. Pat. Nos. 7,488,802,7,943,743, 8,008,449, 8,168,757, 8,217, 149, or 10,308,644; U.S. Publ.Nos. 2017/0145025, 2017/0174671, 2017/0174679, 2017/0320875,2017/0342060, 2017/0362253, 2018/0016260, 2018/0057486, 2018/0177784,2018/0177870, 2018/0179179, 2018/0179201, 2018/0179202, 2018/0273519,2019/0040082, 2019/0062345, 2019/0071439, 2019/0127467, 2019/0144439,2019/0202824, 2019/0225601, 2019/0300524, or 2019/0345170; or PCT Pub.Nos. WO 03042402, WO 2008156712, WO 2010089411, WO 2010036959, WO2011066342, WO 2011159877, WO 2011082400, or WO 2011161699, which areeach incorporated herein by reference in their entirety. In someembodiments, the inhibitor of PD-L1 is INCB086550.

In some embodiments, the antibody is an anti-PD-1 antibody, e.g., ananti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1antibody is nivolumab, pembrolizumab, cemiplimab, spartalizumab,camrelizumab, cetrelimab, toripalimab, sintilimab, AB122, AMP-224,JTX-4014, BGB-108, BCD-100, BAT1306, LZM009, AK105, HLX10, or TSR-042.In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab,cemiplimab, spartalizumab, camrelizumab, cetrelimab, toripalimab, orsintilimab. In some embodiments, the anti-PD-1 antibody ispembrolizumab. In some embodiments, the anti-PD-1 antibody is nivolumab.In some embodiments, the anti-PD-1 antibody is cemiplimab. In someembodiments, the anti-PD-1 antibody is spartalizumab. In someembodiments, the anti-PD-1 antibody is camrelizumab. In someembodiments, the anti-PD-1 antibody is cetrelimab. In some embodiments,the anti-PD-1 antibody is toripalimab. In some embodiments, theanti-PD-1 antibody is sintilimab. In some embodiments, the anti-PD-1antibody is AB122. In some embodiments, the anti-PD-1 antibody isAMP-224. In some embodiments, the anti-PD-1 antibody is JTX-4014. Insome embodiments, the anti-PD-1 antibody is BGB-108. In someembodiments, the anti-PD-1 antibody is BCD-100. In some embodiments, theanti-PD-1 antibody is BAT1306. In some embodiments, the anti-PD-1antibody is LZM009. In some embodiments, the anti-PD-1 antibody isAK105. In some embodiments, the anti-PD-1 antibody is HLX10. In someembodiments, the anti-PD-1 antibody is TSR-042. In some embodiments, theanti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In someembodiments, the anti-PD-1 monoclonal antibody is MGA012 (INCMGA0012;retifanlimab). In some embodiments, the anti-PD1 antibody is SHR-1210.Other anti-cancer agent(s) include antibody therapeutics such as 4-1BB(e.g., urelumab, utomilumab). In some embodiments, the inhibitor of animmune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonalantibody is atezolizumab, avelumab, durvalumab, tislelizumab,BMS-935559, MEDI4736, atezolizumab (MPDL3280A; also known as RG7446),avelumab (MSB0010718C), FAZ053, KN035, CS1001, SHR-1316, CBT-502, A167,STI-A101, CK-301, BGB-A333, MSB-2311, HLX20, or LY3300054. In someembodiments, the anti-PD-L1 antibody is atezolizumab, avelumab,durvalumab, or tislelizumab. In some embodiments, the anti-PD-L1antibody is atezolizumab. In some embodiments, the anti-PD-L1 antibodyis avelumab. In some embodiments, the anti-PD-L1 antibody is durvalumab.In some embodiments, the anti-PD-L1 antibody is tislelizumab. In someembodiments, the anti-PD-L1 antibody is BMS-935559. In some embodiments,the anti-PD-L1 antibody is MEDI4736. In some embodiments, the anti-PD-L1antibody is FAZ053. In some embodiments, the anti-PD-L1 antibody isKN035. In some embodiments, the anti-PD-L1 antibody is CS1001. In someembodiments, the anti-PD-L1 antibody is SHR-1316. In some embodiments,the anti-PD-L1 antibody is CBT-502. In some embodiments, the anti-PD-L1antibody is A167. In some embodiments, the anti-PD-L1 antibody isSTI-A101. In some embodiments, the anti-PD-L1 antibody is CK-301. Insome embodiments, the anti-PD-L1 antibody is BGB-A333. In someembodiments, the anti-PD-L1 antibody is MSB-2311. In some embodiments,the anti-PD-L1 antibody is HLX20. In some embodiments, the anti-PD-L1antibody is LY3300054.

In some embodiments, the inhibitor of an immune checkpoint molecule is asmall molecule that binds to PD-L1, or a pharmaceutically acceptablesalt thereof. In some embodiments, the inhibitor of an immune checkpointmolecule is a small molecule that binds to and internalizes PD-L1, or apharmaceutically acceptable salt thereof. In some embodiments, theinhibitor of an immune checkpoint molecule is a compound selected fromthose in US 2018/0179201, US 2018/0179197, US 2018/0179179, US2018/0179202, US 2018/0177784, US 2018/0177870, U.S. Ser. No. 16/369,654(filed Mar. 29, 2019), and U.S. Ser. No. 62/688,164, or apharmaceutically acceptable salt thereof, each of which is incorporatedherein by reference in its entirety.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of KIR, TIGIT, LAIR1, CD160, 2B4 and TGFR beta.

In some embodiments, the inhibitor is MCLA-145.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab,AGEN1884, or CP-675,206.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016, LAG525, INCAGN2385, or eftilagimodalpha (IMP321).

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD73. In some embodiments, the inhibitor of CD73 isoleclumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIGIT. In some embodiments, the inhibitor of TIGIT isOMP-31M32.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of VISTA. In some embodiments, the inhibitor of VISTA isJNJ-61610588 or CA-170.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of B7-H3. In some embodiments, the inhibitor of B7-H3 isenoblituzumab, MGD009, or 8H9.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of KIR. In some embodiments, the inhibitor of KIR islirilumab or IPH4102.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of A2aR. In some embodiments, the inhibitor of A2aR isCPI-444.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TGF-beta. In some embodiments, the inhibitor of TGF-betais trabedersen, galusertinib, or M7824.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PI3K-gamma. In some embodiments, the inhibitor ofPI3K-gamma is IPI-549.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD47. In some embodiments, the inhibitor of CD47 isHu5F9-G4 or TTI-621.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD73. In some embodiments, the inhibitor of CD73 isMEDI9447.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD70. In some embodiments, the inhibitor of CD70 iscusatuzumab or BMS-936561.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of OX40, CD27, CD28, GITR, ICOS, CD40, TLR7/8, and CD137 (alsoknown as 4-1BB).

In some embodiments, the agonist of CD137 is urelumab. In someembodiments, the agonist of CD137 is utomilumab.

In some embodiments, the agonist of an immune checkpoint molecule is aninhibitor of GITR. In some embodiments, the agonist of GITR is TRX518,MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, MEDI1873, orMEDI6469. In some embodiments, the agonist of an immune checkpointmolecule is an agonist of OX40, e.g., OX40 agonist antibody or OX40Lfusion protein. In some embodiments, the anti-OX40 antibody isINCAGN01949, MEDI0562 (tavolimab), MOXR-0916, PF-04518600, GSK3174998,BMS-986178, or 9B12. In some embodiments, the OX40L fusion protein isMEDI6383.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of CD40. In some embodiments, the agonist of CD40 is CP-870893,ADC-1013, CDX-1140, SEA-CD40, RO7009789, JNJ-64457107, APX-005M, or ChiLob 7/4.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of ICOS. In some embodiments, the agonist of ICOS isGSK-3359609, JTX-2011, or MEDI-570.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of CD28. In some embodiments, the agonist of CD28 istheralizumab.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of CD27. In some embodiments, the agonist of CD27 is varlilumab.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of TLR7/8. In some embodiments, the agonist of TLR7/8 isMEDI9197.

The compounds of the present disclosure can be used in combination withbispecific antibodies. In some embodiments, one of the domains of thebispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3,CD137, ICOS, CD3 or TGF.beta. receptor. In some embodiments, thebispecific antibody binds to PD-1 and PD-L1. In some embodiments, thebispecific antibody that binds to PD-1 and PD-L1 is MCLA-136. In someembodiments, the bispecific antibody binds to PD-L1 and CTLA-4. In someembodiments, the bispecific antibody that binds to PD-L1 and CTLA-4 isAK104.

In some embodiments, the compounds of the disclosure can be used incombination with one or more metabolic enzyme inhibitors. In someembodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1,TDO, or arginase. Examples of IDO1 inhibitors include epacadostat,NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196.Inhibitors of arginase inhibitors include INCB1158.

As provided throughout, the additional compounds, inhibitors, agents,etc. can be combined with the present compound in a single or continuousdosage form, or they can be administered simultaneously or sequentiallyas separate dosage forms.

II. Cancer Therapies

Cancer cell growth and survival can be impacted by multiple signalingpathways. Thus, it is useful to combine differentenzyme/protein/receptor inhibitors, exhibiting different preferences inthe targets which they modulate the activities of, to treat suchconditions. Examples of agents that may be combined with compounds ofthe present disclosure, or solid forms or salts thereof, includeinhibitors of the PI3K-AKT-mTOR pathway, inhibitors of the Raf-MAPKpathway, inhibitors of JAK-STAT pathway, inhibitors of beta cateninpathway, inhibitors of notch pathway, inhibitors of hedgehog pathway,inhibitors of Pim kinases, and inhibitors of protein chaperones and cellcycle progression. Targeting more than one signaling pathway (or morethan one biological molecule involved in a given signaling pathway) mayreduce the likelihood of drug-resistance arising in a cell population,and/or reduce the toxicity of treatment.

The compounds of the present disclosure, or solid forms or saltsthereof, can be used in combination with one or more otherenzyme/protein/receptor inhibitors for the treatment of diseases, suchas cancer. Examples of cancers include solid tumors and liquid tumors,such as blood cancers. For example, the compounds of the presentdisclosure, or solid forms or salts thereof, can be combined with one ormore inhibitors of the following kinases for the treatment of cancer:Akt1, Akt2, Akt3, TGF-□R, PKA, PKG, PKC, CaM-kinase, phosphorylasekinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R,IR-R, PDGFαR, PDGFβR, CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, fit-1,FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3,VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn,Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-Raf. In someembodiments, the compounds of the present disclosure, or solid forms orsalts thereof, can be combined with one or more of the followinginhibitors for the treatment of cancer.

Non-limiting examples of inhibitors that can be combined with thecompounds of the present disclosure, or solid forms or salts thereof,for treatment of cancers include an FGFR inhibitor (FGFR1, FGFR2, FGFR3or FGFR4, e.g., AZD4547, BAY1187982, ARQ087, BGJ398, BIBF1120, TKI258,lucitanib, dovitinib, TAS-120, JNJ-42756493, Debiol347, INCB54828,INCB62079 and INCB63904), a JAK inhibitor (JAK1 and/or JAK2, e.g.,ruxolitinib, baricitinib or INCB39110), an IDO inhibitor (e.g.,epacadostat and NLG919), an LSD1 inhibitor (e.g., GSK2979552, INCB59872and INCB60003), a TDO inhibitor, a PI3K-delta inhibitor (e.g., INCB50797and INCB50465), a PI3K-gamma inhibitor such as a PI3K-gamma selectiveinhibitor, a CSF1R inhibitor (e.g., PLX3397 and LY3022855), a TAMreceptor tyrosine kinases (Tyro-3, Axl, and Mer), an angiogenesisinhibitor, an interleukin receptor inhibitor, bromo and extra terminalfamily members inhibitors (for example, bromodomain inhibitors or BETinhibitors such as OTX015, CPI-0610, INCB54329 and INCB57643) and anadenosine receptor antagonist or combinations thereof. Inhibitors ofHDAC such as panobinostat and vorinostat. Inhibitors of c-Met such asonartumzumab, tivantnib, and INC-280. Inhibitors of BTK such asibrutinib. Inhibitors of mTOR such as rapamycin, sirolimus,temsirolimus, and everolimus. Inhibitors of Raf, such as vemurafenib anddabrafenib. Inhibitors of MEK such as trametinib, selumetinib andGDC-0973. Inhibitors of Hsp90 (e.g., tanespimycin), cyclin dependentkinases (e.g., palbociclib), PARP (e.g., olaparib) and Pim kinases(LGH447, INCB053914 and SGI-1776) can also be combined with compounds ofthe present disclosure.

Compounds of the present disclosure, or solid forms or salts thereof,can be used in combination with one or more agents for the treatment ofdiseases such as cancer. In some embodiments, the agent is an alkylatingagent, a proteasome inhibitor, a corticosteroid, or an immunomodulatoryagent. Examples of an alkylating agent include bendamustine, nitrogenmustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas andtriazenes, uracil mustard, chlormethine, cyclophosphamide (Cytoxan™),ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine,triethylenethiophosphoramine, busulfan, carmustine, lomustine,streptozocin, dacarbazine, and temozolomide. In some embodiments, theproteasome inhibitor is carfilzomib. In some embodiments, thecorticosteroid is dexamethasone (DEX). In some embodiments, theimmunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM).

The compounds of the present disclosure, or solid forms or saltsthereof, can further be used in combination with other methods oftreating cancers, for example by chemotherapy, irradiation therapy,tumor-targeted therapy, adjuvant therapy, immunotherapy or surgery.Examples of immunotherapy include cytokine treatment (e.g., interferons,GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccine, monoclonalantibody, adoptive T cell transfer, CAR (Chimeric antigen receptor) Tcell treatment as a booster for T cell activation, oncolytic virotherapyand immunomodulating small molecules, including thalidomide or JAK1/2inhibitor and the like. The compounds can be administered in combinationwith one or more anti-cancer drugs, such as a chemotherapeutics. Examplechemotherapeutics include any of: abarelix, abiraterone, afatinib,aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol,altretamine, amsacrine, anastrozole, aphidicolon, arsenic trioxide,asparaginase, axitinib, azacitidine, bevacizumab, bexarotene,baricitinib, bicalutamide, bleomycin, bortezombi, bortezomib, brivanib,buparlisib, busulfan intravenous, busulfan oral, calusterone, camptosar,capecitabine, carboplatin, carmustine, cediranib, cetuximab,chlorambucil, cisplatin, cladribine, clofarabine, crizotinib,cyclophosphamide, cytarabine, dacarbazine, dacomitinib, dactinomycin,dalteparin sodium, dasatinib, dactinomycin, daunorubicin, decitabine,degarelix, denileukin, denileukin diftitox, deoxycoformycin,dexrazoxane, docetaxel, doxorubicin, droloxafine, dromostanolonepropionate, eculizumab, enzalutamide, epidophyllotoxin, epirubicin,epothilones, erlotinib, estramustine, etoposide phosphate, etoposide,exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine,fluorouracil, flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumabozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan,idarubicin, idelalisib, ifosfamide, imatinib mesylate, interferon alfa2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole,leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine,megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen,mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolonephenpropionate, navelbene, necitumumab, nelarabine, neratinib,nilotinib, nilutamide, nofetumomab, oserelin, oxaliplatin, paclitaxel,pamidronate, panitumumab, pazopanib, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pilaralisib, pipobroman, plicamycin,ponatinib, porfimer, prednisone, procarbazine, quinacrine, ranibizumab,rasburicase, regorafenib, reloxafine, revlimid, rituximab, ruxolitinib,sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen,tegafur, temozolomide, teniposide, testolactone, thalidomide,thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab,tretinoin, triptorelin, uracil mustard, valrubicin, vandetanib,vinblastine, vincristine, vindesine, vinorelbine, vorinostat andzoledronate.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4 (e.g., ipilimumab or tremelimumab), 4-1BB, antibodies to PD-1 andPD-L1, or antibodies to cytokines (IL-10, TGF-β, etc.). Examples ofantibodies to PD-1 and/or PD-L1 that can be combined with compounds ofthe present disclosure for the treatment of cancer or infections such asviral, bacteria, fungus and parasite infections include, but are notlimited to, nivolumab, pembrolizumab, MPDL3280A, MEDI-4736 and SHR-1210.

Other anti-cancer agents include inhibitors of kinases associated cellproliferative disorder. These kinases include but not limited toAurora-A, CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9, ephrin receptorkinases, CHK1, CHK2, SRC, Yes, Fyn, Lck, Fer, Fes, Syk, Itk, Bmx, GSK3,JNK, PAK1, PAK2, PAK3, PAK4, PDK1, PKA, PKC, Rsk, and SGK.

Other anti-cancer agents also include those that block immune cellmigration such as antagonists to chemokine receptors, including CCR2 andCCR4.

The compounds of the present disclosure, or solid forms or saltsthereof, can further be used in combination with one or moreanti-inflammatory agents, steroids, immunosuppressants or therapeuticantibodies. The steroids include but are not limited to 17alpha-ethinylestradiol, diethylstilbestrol, testosterone, prednisone,fluoxymesterone, methylprednisolone, methyltestosterone, prednisolone,triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide,and medroxyprogesteroneacetate.

The compounds of the present disclosure, or solid forms or saltsthereof, can also be used in combination with lonafarnib (SCH6636),tipifarnib (R115777), L778123, BMS 214662, tezacitabine (MDL 101731),Sml1, triapine, didox, trimidox and amidox.

The compounds of the disclosure, or salts or solid forms thereof, can becombined with another immunogenic agent, such as cancerous cells,purified tumor antigens (including recombinant proteins, peptides, andcarbohydrate molecules), cells, and cells transfected with genesencoding immune stimulating cytokines. Non-limiting examples of tumorvaccines that can be used include peptides of melanoma antigens, such aspeptides of gp100, MAGE antigens, Trp-2, MARTI and/or tyrosinase, ortumor cells transfected to express the cytokine GM-CSF.

The compounds of the present disclosure, or solid forms or saltsthereof, can be used in combination with a vaccination protocol for thetreatment of cancer. In some embodiments, the tumor cells are transducedto express GM-CSF. In some embodiments, tumor vaccines include theproteins from viruses implicated in human cancers such as HumanPapilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) and Kaposi'sHerpes Sarcoma Virus (KHSV). In some embodiments, the compounds of thepresent disclosure, or solid forms or salts thereof, can be used incombination with tumor specific antigen such as heat shock proteinsisolated from tumor tissue itself. In some embodiments, the compounds ofthe present disclosure, or solid forms or salts thereof, can be combinedwith dendritic cells immunization to activate potent anti-tumorresponses.

The compounds of the present disclosure, or solid forms or saltsthereof, can be used in combination with bispecific macrocyclic peptidesthat target Fe alpha or Fe gamma receptor-expressing effectors cells totumor cells. The compounds of the present disclosure, or solid forms orsalts thereof, can also be combined with macrocyclic peptides thatactivate host immune responsiveness.

The compounds of the present disclosure, or solid forms or saltsthereof, can be used in combination with bone marrow transplant for thetreatment of a variety of tumors of hematopoietic origin.

Suitable antiviral agents contemplated for use in combination with thecompounds of the present disclosure can comprise nucleoside andnucleotide reverse transcriptase inhibitors (NRTIs), non-nucleosidereverse transcriptase inhibitors (NNRTIs), protease inhibitors and otherantiviral drugs.

Example suitable NRTIs include zidovudine (AZT); didanosine (ddl);zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir(1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194);BCH-10652; emitricitabine [(−)-FTC]; beta-L-FD4 (also called beta-L-D4Cand named beta-L-2′, 3′-dicleoxy-5-fluoro-cytidene); DAPD,((−)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA).Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine(BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione);and (+)-calanolide A (NSC-675451) and B. Typical suitable proteaseinhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538);indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir(BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1 549. Otherantiviral agents include hydroxyurea, ribavirin, IL-2, IL-12,pentafuside and Yissum Project No. 11607.

When more than one pharmaceutical agent is administered to a patient,they can be administered simultaneously, separately, sequentially, or incombination (e.g., for more than two agents).

In some embodiments, the compounds of the present disclosure, or solidforms or salts thereof, can be used in combination with INCB086550.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the disclosure can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral, or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be, forexample, by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This disclosure also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the disclosure or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the disclosure, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

The compounds of the disclosure may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the disclosure can beprepared by processes known in the art, e.g., see International App. No.WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the disclosure can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1000 mg (1 g), more usually about 100to about 500 mg, of the active ingredient. The term “unit dosage forms”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient.

In some embodiments, the compositions of the disclosure contain fromabout 5 to about 50 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 5 to about 10, about 10 to about 15, about 15 to about20, about 20 to about 25, about 25 to about 30, about 30 to about 35,about 35 to about 40, about 40 to about 45, or about 45 to about 50 mgof the active ingredient.

In some embodiments, the compositions of the disclosure contain fromabout 50 to about 500 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 50 to about 100, about 100 to about 150, about 150 toabout 200, about 200 to about 250, about 250 to about 300, about 350 toabout 400, or about 450 to about 500 mg of the active ingredient.

In some embodiments, the compositions of the disclosure contain fromabout 500 to about 1000 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 500 to about 550, about 550 to about 600, about 600 toabout 650, about 650 to about 700, about 700 to about 750, about 750 toabout 800, about 800 to about 850, about 850 to about 900, about 900 toabout 950, or about 950 to about 1000 mg of the active ingredient.

Similar dosages may be used of the compounds described herein in themethods and uses of the disclosure.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present disclosure. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, about 0.1 to about 1000 mg of the activeingredient of the present disclosure.

The tablets or pills of the present disclosure can be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action. For example, the tablet or pill can comprise an innerdosage and an outer dosage component, the latter being in the form of anenvelope over the former. The two components can be separated by anenteric layer which serves to resist disintegration in the stomach andpermit the inner component to pass intact into the duodenum or to bedelayed in release. A variety of materials can be used for such entericlayers or coatings, such materials including a number of polymeric acidsand mixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentdisclosure can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.

Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, for example, liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, for example,glycerol, hydroxyethyl cellulose, and the like. In some embodiments,topical formulations contain at least about 0.1, at least about 0.25, atleast about 0.5, at least about 1, at least about 2, or at least about 5wt % of the compound of the disclosure. The topical formulations can besuitably packaged in tubes of, for example, 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present disclosure can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of a compound of the disclosure in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of thedisclosure can be provided in an aqueous physiological buffer solutioncontaining about 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.

Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

The compositions of the disclosure can further include one or moreadditional pharmaceutical agents such as a chemotherapeutic, steroid,anti-inflammatory compound, or immunosuppressant, examples of which arelisted herein.

Labeled Compounds and Assay Methods

Another aspect of the present disclosure relates to labeled compounds ofthe disclosure (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating DGK in tissue samples,including human, and for identifying DGK inhibitors by binding of alabeled compound. Substitution of one or more of the atoms of thecompounds of the present disclosure can also be useful in generatingdifferentiated ADME (Adsorption, Distribution, Metabolism andExcretion.) Accordingly, the present disclosure includes DGK assays thatcontain such labeled or substituted compounds.

The present disclosure further includes isotopically-labeled compoundsof the disclosure. An “isotopically” or “radio-labeled” compound is acompound of the disclosure where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present disclosure include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. For example, one or more hydrogenatoms in a compound of the present disclosure can be replaced bydeuterium atoms (e.g., one or more hydrogen atoms of a C₁₋₆ alkyl groupof Formula I can be optionally substituted with deuterium atoms, such as—CD₃ being substituted for —CH₃). In some embodiments, alkyl groups ofthe disclosed Formulas (e.g., Formula I) can be perdeuterated.

One or more constituent atoms of the compounds presented herein can bereplaced or substituted with isotopes of the atoms in natural ornon-natural abundance. In some embodiments, the compound includes atleast one deuterium atom. For example, one or more hydrogen atoms in acompound presented herein can be replaced or substituted by deuterium(e.g., one or more hydrogen atoms of a C₁₋₆ alkyl group can be replacedby deuterium atoms, such as —CD₃ being substituted for —CH₃). In someembodiments, the compound includes two or more deuterium atoms. In someembodiments, the compound includes 1-2, 1-3, 1-4, 1-5, 1-6, 1-8, 1-10,1-12, 1-14, 1-16, 1-18, or 1-20 deuterium atoms. In some embodiments,all of the hydrogen atoms in a compound can be replaced or substitutedby deuterium atoms.

In some embodiments, each hydrogen atom of the compounds providedherein, such as hydrogen atoms attached to carbon atoms of alkyl,alkenyl, alkynyl, aryl, phenyl, cycloalkyl, heterocycloalkyl, orheteroaryl substituents or —C₁₋₄ alkyl-, alkylene, alkenylene, andalkynylene linking groups, as described herein, is optionally replacedby deuterium atoms.

In some embodiments, each hydrogen atom of the compounds providedherein, such as hydrogen atoms to carbon atoms of alkyl, alkenyl,alkynyl, aryl, phenyl, cycloalkyl, heterocycloalkyl, or heteroarylsubstituents or —C₁₋₄ alkyl-, alkylene, alkenylene, and alkynylenelinking groups, as described herein, is replaced by deuterium atoms(i.e., the alkyl, alkenyl, alkynyl, aryl, phenyl, cycloalkyl,heterocycloalkyl, or heteroaryl substituents, or —C₁₋₄ alkyl-, alkylene,alkenylene, and alkynylene linking groups are perdeuterated).

In some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hydrogenatoms, attached to carbon atoms of alkyl, alkenyl, alkynyl, aryl,phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl substituents or—C₁₋₄ alkyl-, alkylene, alkenylene, and alkynylene linking groups, asdescribed herein, are optionally replaced by deuterium atoms.

In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms, attachedto carbon atoms of alkyl, alkenyl, alkynyl, aryl, phenyl, cycloalkyl,heterocycloalkyl, or heteroaryl substituents or —C₁₋₄ alkyl-, alkylene,alkenylene, and alkynylene linking groups, as described herein, areoptionally replaced by deuterium atoms.

In some embodiments, the compound provided herein (e.g., the compound ofany of Formulas I-VII), or a pharmaceutically acceptable salt thereof,comprises at least one deuterium atom.

In some embodiments, the compound provided herein (e.g., the compound ofany of Formulas I-VII), or a pharmaceutically acceptable salt thereof,comprises two or more deuterium atoms.

In some embodiments, the compound provided herein (e.g., the compound ofany of Formulas I-VII), or a pharmaceutically acceptable salt thereof,comprises three or more deuterium atoms.

In some embodiments, for a compound provided herein (e.g., the compoundof any of Formulas I-VII), or a pharmaceutically acceptable saltthereof, all of the hydrogen atoms are replaced by deuterium atoms(i.e., the compound is “perdeuterated”).

Synthetic methods for including isotopes into organic compounds areknown in the art (Deuterium Labeling in Organic Chemistry by Alan F.Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissanceof H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and JochenZimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistryof Isotopic Labelling by James R. Hanson, Royal Society of Chemistry,2011). Isotopically labeled compounds can be used in various studiessuch as NMR spectroscopy, metabolism experiments, and/or assays.

Substitution with heavier isotopes, such as deuterium, may affordcertain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances. (seee.g., A. Kerekes et. al. J. Med. Chem. 2011, 54, 201-210; R. Xu et. al.J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular,substitution at one or more metabolism sites may afford one or more ofthe therapeutic advantages.

The radionuclide that is incorporated in the instant radio-labeledcompounds will depend on the specific application of that radio-labeledcompound. For example, for in vitro DGK labeling and competition assays,compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I or ³⁵S can beuseful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I,⁷⁵Br, ⁷⁶Br or ⁷⁷Br can be useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments, the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

The present disclosure can further include synthetic methods forincorporating radio-isotopes into compounds of the disclosure. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of disclosure.

A labeled compound of the disclosure can be used in a screening assay toidentify/evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind DGK by monitoring its concentrationvariation when contacting with DGK, through tracking of the labeling.For example, a test compound (labeled) can be evaluated for its abilityto reduce binding of another compound which is known to bind to DGK(i.e., standard compound). Accordingly, the ability of a test compoundto compete with the standard compound for binding to DGK directlycorrelates to its binding affinity. Conversely, in some other screeningassays, the standard compound is labeled and test compounds areunlabeled. Accordingly, the concentration of the labeled standardcompound is monitored in order to evaluate the competition between thestandard compound and the test compound, and the relative bindingaffinity of the test compound is thus ascertained.

Kits

The present disclosure also includes pharmaceutical kits useful, forexample, in the treatment or prevention of DGK-associated diseases ordisorders as described herein, which include one or more containerscontaining a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of the disclosure. Such kits can furtherinclude, if desired, one or more of various conventional pharmaceuticalkit components, such as, for example, containers with one or morepharmaceutically acceptable carriers, additional containers, etc., aswill be readily apparent to those skilled in the art. Instructions,either as inserts or as labels, indicating quantities of the componentsto be administered, guidelines for administration, and/or guidelines formixing the components, can also be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results.

EXAMPLES

Preparatory LC-MS purifications of some of the compounds prepared wereperformed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature (see e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004)). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity analysis under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ Cis 5μm, 2.1×50 mm, Buffers: mobile phase A: 0.025% TFA in water and mobilephase B: acetonitrile; gradient 2% to 80% of B in 3 minutes with flowrate 2.0 m/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm, 19×100 mm, eluting withmobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobilephase B: acetonitrile; the flow rate was 30 m/minute, the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature (see e.g.“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)). For purifications using a 30×100 mm column, the flowrate was 60 m/minute.

pH=10 purifications: Waters XBridge™ C₁₈ 5 μm, 19×100 mm column, elutingwith mobile phase A: 0.15% NH₄OH in water and mobile phase B:acetonitrile; the flow rate was 30 m/minute, the separating gradient wasoptimized for each compound using the Compound Specific MethodOptimization protocol as described in the literature (see e.g.“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)). For purifications using a 30×100 mm column, the flowrate was 60 mL/minute.

Intermediate 1.8-Hydroxy-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile

Step 1. Ethyl 3-acetamido-6-bromopicolinate

To a mixture of ethyl 3-amino-6-bromopicolinate (5.00 g, 20.4 mmol,Combi-Blocks QH-5934) in THF (40 mL) was added acetic anhydride (19.3mL, 204 mmol) and the reaction mixture was stirred at 90° C. overnight.After cooling to rt, the reaction mixture was concentrated in vacuo. Tothe crude residue was added EtOAc (10 mL) followed by Et₂O (30 mL) andhexanes (200 mL) and the mixture was slurried for 30 mins. The solidprecipitate was collected via vacuum filtration, washed with hexanes,and dried under air to afford the desired product (4.35 g, 74% yield) asan off-white solid.

LC-MS calculated for C₁₀H₁₂BrN₂O₃ (M+H)⁺: m/z=287.0; found 287.1.

Step 2. Ethyl 3-acetamido-6-cyanopicolinate

In a microwave vial with a stir bar, a mixture of ethyl3-acetamido-6-bromopicolinate (1.7 g, 5.9 mmol) and copper(I) cyanide(0.80 g, 8.9 mmol) in DMF (15 mL) in a reaction vial was irradiated in amicrowave reactor at 200° C. for 8 min. After cooling to rt, thereaction mixture was diluted with CH₂Cl₂ and water and the insolublematerial was removed via filtration. The filtrate was transferred to aseparatory funnel and after phase separation the organic phase wasremoved and the aqueous phase was extracted twice more with CH₂Cl₂. Thecombined organic phases were washed with sat. aq. NaCl, dried overMgSO₄, and concentrated. The crude residue was purified by flash columnchromatography (SiO₂, EtOAc/hexanes) to afford the desired product (0.84g, 61% yield). LC-MS calculated for C₁₁H₁₂N₃O₃ (M+H)⁺: m/z=234.1; found234.0.

Step 3. Ethyl 6-cyano-3-(N-methylacetamido)picolinate

A mixture of ethyl 3-acetamido-6-cyanopicolinate (2.40 g, 10.3 mmol),cesium carbonate (7.38 g, 22.64 mmol) and methyl iodide (1.3 mL, 20.6mmol) in DMF (50 mL) was stirred at rt for 3 hours. The reaction mixturewas diluted with CH₂Cl₂ and sat. aq. NaCl and shaken in a separatoryfunnel. After phase separation, the organic phase was removed and theaqueous phase was extracted once more with CH₂Cl₂. The combined organicsolution was dried over Na₂SO₄ and concentrated. The crude residue waspurified by flash column chromatography (SiO₂, EtOAc/hexanes) to affordthe desired product (2.24 g, 88% yield). LC-MS calculated for C₁₂H₁₄N₃O₃(M+H)⁺: m/z=248.1; found 248.1.

Step 4.8-Hydroxy-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile

A mixture ethyl 6-cyano-3-(N-methylacetamido)picolinate (0.82 g, 3.3mmol) in anhydrous THF (30 ml) was cooled to −78° C. in a dryice/acetone bath before a 0.5 molar solution of potassiumbis(trimethylsilyl)amide in toluene (8 mL, 4 mmol, Aldrich 277304) wasadded dropwise over ca. 30 min. The reaction mixture was stirred at −78°C. for an additional 20 min before the dry ice/acetone bath was removedand the mixture was stirred at rt for 1 h. The reaction was diluted withH₂O and extracted with EtOAc. After phase separation, the aqueous phasewas removed and acidified with 1 molar aq. HCl. The fine yellowprecipitate that formed was collected via filtration, washed with H₂O (2mL), and dried under vacuum to afford the desired product (0.47 g, 70%yield).

LC-MS calculated for C₁₀H₈N₃O₂ (M+H)⁺: m/z=202.1; found 202.1.

Intermediate 2.6-Cyano-1-methyl-3-nitro-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yltrifluoromethanesulfonate

Step 1.8-Hydroxy-5-methyl-7-nitro-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile

To a mixture of8-hydroxy-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile(Intermediate 1, 603 mg, 3.0 mmol) in AcOH (3.0 mL) was added nitricacid (0.4 mL, 9 mmol) and the mixture was stirred at 100° C. for 30 min.After cooling to rt, the mixture was diluted with ice water (30 mL) andslurried for 30 mins. The solid precipitate that formed was collectedvia filtration, washed with water, and dried under air to afford thedesired product (492 mg, 67% yield) as a yellow solid. The crudematerial obtained was used directly without further purification. LC-MScalculated for C₁₀H₇N₄O₄ (M+H)⁺: m/z=247.0; found 247.0.

Step 2. 6-Cyano-1-methyl-3-nitro-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yltrifluoromethanesulfonate

In an oven-dried microwave vial with a stir bar, a mixture of8-hydroxy-5-methyl-7-nitro-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile(492 mg, 2.00 mmol) in CH₂Cl₂ (10 mL) was irradiated in a microwavereactor at 70° C. for 15 mins. After cooling to rt,4-dimethylaminopyridine (24.2 mg, 0.20 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.57 mL, 3.3 mmol) were added and themixture was purged with nitrogen and cooled to 0° C. in an ice bathbefore trifluoromethanesulfonic anhydride (0.5 mL, 3 mmol, Aldrich176176) was added dropwise. The ice bath was removed and the mixture wasstirred at rt for 4 h. The reaction mixture was diluted with sat. aq.NaHCO₃ and extracted with CH₂Cl₂. The combined organic phases were driedover MgSO₄ and concentrated. The crude material obtained was useddirectly without further purification. LC-MS calculated for C₁₁H₆F₃N₄O₆S(M+H)⁺: m/z=379.0; found 379.1.

Intermediate 3.(8aR,11R)-10-(Bis(4-fluorophenyl)methyl)-5,11-dimethyl-6,8-dioxo-5,7,8,8a,9,10,11,12-octahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-2-carbonitrile

Step 1. 1-(tert-Butyl) 3-methyl(3R,6R)-4-(6-cyano-1-methyl-3-nitro-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-6-methylpiperazine-1,3-dicarboxylate

To a mixture of6-cyano-1-methyl-3-nitro-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yltrifluoromethanesulfonate (Intermediate 2, 0.75 g, 2.0 mmol) and1-(tert-butyl) 3-methyl (3R,6R)-6-methylpiperazine-1,3-dicarboxylate(542 mg, 2.098 mmol, Ambeed A1152532) in CH₃CN (10 mL) was addedN-ethyl-N-isopropylpropan-2-amine (1.04 mL, 6.0 mmol) and the reactionmixture was stirred at 85° C. overnight. After cooling to rt, thereaction mixture was concentrated in vacuo and the crude residue waspurified directly using flash column chromatography (40 g SiO₂,EtOAc/hexanes) to afford the desired product (876 mg, 90% yield) as areddish-orange foamy solid. LC-MS calculated for C₂₂H₂₆N₆O₇Na (M+Na)⁺:m/z=509.2; found 509.1.

Step 2. tert-Butyl(8aR,11R)-2-cyano-5,11-dimethyl-6,8-dioxo-5,6,7,8,8a,9,11,12-octahydro-10H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-10-carboxylate

A mixture of 1-(tert-butyl) 3-methyl(3R,6R)-4-(6-cyano-1-methyl-3-nitro-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-6-methylpiperazine-1,3-dicarboxylate(876 mg, 1.8 mmol), iron (500 mg, 9 mmol), and ammonium chloride (960mg, 18 mmol) in a 1:1:1 mixture of THF/MeOH/H₂O (9 mL) was stirred at80° C. for 4 h. After cooling to rt, the mixture was diluted with sat.aq. NaCl and extracted with CH₂Cl₂. The combined organic phases weredried over MgSO₄, concentrated, and the crude residue was purified usingflash column chromatography (24 g SiO₂, EtOAc/hexanes). Fractionscontaining the desired product were concentrated and the solid residuewas triturated with THF/hexanes to afford the desired product (192 mg,25% yield) as a yellow solid. LC-MS calculated for C₂₁H₂₄N₆O₄Na (M+Na)⁺:m/z=447.2; found 447.2.

Step 3.(8aR,11R)-5,11-Dimethyl-6,8-dioxo-5,7,8,8a,9,10,11,12-octahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-2-carbonitrilehydrochloride

To a mixture of tert-butyl(8aR,11R)-2-cyano-5,11-dimethyl-6,8-dioxo-5,6,7,8,8a,9,11,12-octahydro-10H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-10-carboxylate(192 mg, 0.45 mmol) in THF (2.3 mL) was added a 4 molar solution of HClin 1,4-dioxane (1.1 mL, 4.5 mmol) and the reaction mixture was purgedwith N₂ and stirred at rt overnight. The reaction mixture wasconcentrated in vacuo, and the crude material obtained was used directlywithout further purification. LC-MS calculated for C₁₆H₁₇N₆O₂ (M+H)⁺:m/z=325.1; found 325.3.

Step 4.(8aR,11R)-10-(Bis(4-fluorophenyl)methyl)-5,11-dimethyl-6,8-dioxo-5,7,8,8a,9,10,11,12-octahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-2-carbonitrile

A mixture of(8aR,11R)-5,11-dimethyl-6,8-dioxo-5,7,8,8a,9,10,11,12-octahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-2-carbonitrile(Step 3), 4,4′-(chloromethylene)bis(fluorobenzene) (107 mg, 0.45 mmol,Combi-Blocks QA-4728), and N-ethyl-N-isopropylpropan-2-amine (0.26 mL,1.5 mmol) in CH₃CN (2.3 mL) was stirred at 85° C. for 8 h. After coolingto rt, the reaction mixture was concentrated in vacuo and the cruderesidue was purified by flash column chromatography (12 g SiO₂,EtOAc/hexanes). LC-MS calculated for C₂₉H₂₅F₂N₆O₂ (M+H)⁺: m/z=527.2;found 545.2.

Intermediate 4.(8aR,11R)-10-(Bis(4-fluorophenyl)methyl)-2-bromo-5,7,11-trimethyl-5,7,9,10,11,12-hexahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-6,8(8aH)-dione

Step 1. Methyl 3-acetamido-6-bromopicolinate

To a mixture of methyl 3-amino-6-bromopicolinate (0.50 g, 2.164 mmol) inTHF (6.00 ml) was added acetic anhydride (2.209 g, 21.64 mmol), and thereaction mixture was stirred at 90° C. overnight. After cooling to rt,the reaction mixture was concentrated in vacuo. To the crude residue wasadded EtOAc (2 mL) followed by Et₂O (3 mL) and hexanes (20 mL), and themixture was slurried for 30 mins. The solid precipitate was collectedvia vacuum filtration, washed with hexanes, and dried under air toafford the desired product (0.40 g, 68% yield) as off-white solid. LC-MScalculated for C₉H₁₀BrN₂O₃ (M+H)⁺: m/z=273.0; found 273.1.

Step 2. Methyl 6-bromo-3-(N-methylacetamido)picolinate

To a mixture of ethyl 3-acetamidopicolinate (2.73 g, 10.00 mmol) andcesium carbonate (3.91 g, 12.00 mmol) in N,N-dimethylformamide (10 ml),methyl iodide (813 μL, 13.0 mmol) was added dropwise, and the reactionwas stirred at rt overnight. Then the mixture was diluted with water,extracted with Et₂O, washed with brine, and dried over Na₂SO₄. Afterremoval of the solvent, the crude was purified by flash columnchromatography (12 g SiO₂, EtOAc/hexanes) to afford the desired product(2.4 g, 84% yield) as white solid. LC-MS calculated for C₁₀H₁₂BrN₂O₃(M+H)⁺: m/z=287.0; found 286.9.

Step 3. 6-Bromo-4-hydroxy-1-methyl-1,5-naphthyridin-2(1H)-one

At −78° C. to a mixture of methyl6-bromo-3-(N-methylacetamido)picolinate (574 mg, 2.0 mmol) in THF (10.0mL) was added dropwise a solution of potassium bis(trimethylsilyl)amide(2.4 ml, 2.4 mmol) within about 10 min. After stirring at −78° C. for 20min, the dry ice-acetone bath was removed. The mixture was warmed to rtand stirred at rt for 1 h. EtOAc and water were then added and themixture was transferred to a separation funnel and additional EtOAc wasadded. The aqueous layer was collected and acidified with 1 N HCl to pH2-3. A yellow precipitate formed and the resulting solid was filtered,washed with water and ether, and dried under air afforded desiredproduct (420 mg, 82% yield). LC-MS calculated for C₉H₈BrN₂O₂ (M+H)⁺:m/z=255.0; found 254.9.

Step 4. 6-Bromo-4-hydroxy-1-methyl-3-nitro-1,5-naphthyridin-2(1H)-one

A mixture of 6-bromo-4-hydroxy-1-methyl-1,5-naphthyridin-2(1H)-one (255mg, 1.00 mmol) in nitric acid (1.0 mL) was stirred at rt for 10 minbefore the reaction mixture was heated to 75° C. for 15 min. Aftercooling to rt, ice-water was added to the reaction mixture toprecipitate the product. The yellow solid precipitate was collected viafiltration and, washed with ice-water and cold ethanol, and dried undervacuum to obtain the desired product (200 mg, 67% yield) as yellowsolid. LC-MS calculated for C₉H₇BrN₃O₄ (M+H)⁺: m/z=300.0; found 299.9.

Step 5. 6-Bromo-1-methyl-3-nitro-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yltrifluoromethanesulfonate

A mixture of6-bromo-4-hydroxy-1-methyl-3-nitro-1,5-naphthyridin-2(1H)-one (120 mg,0.40 mmol) (120 mg, 0.40 mmol) and 4-dimethylaminopyridine (6.4 mg,0.052 mmol) in CH₂Cl₂ (2.0 mL) was irradiated in a microwave reactor at70° C. for 15 mins. The reaction mixture was cooled to 0° C. in an icebath before N-ethyl-N-isopropylpropan-2-amine (0.11 mL, 0.82 mmol) andtrifluoromethanesulfonic anhydride (0.10 mL, 0.75 mmol) were addeddropwise. The ice bath was removed and the mixture was stirred at rt for3 h. The reaction was quenched via the addition of sat. aq. NaHCO₃ andextracted with CH₂Cl₂. The combined organic phases were dried overNa₂SO₄ and concentrated to afford the desired product as brown solid.The crude material was used directly without further purification. LC-MScalculated for C₁₀H₆BrF₃N₃O₆S (M+H)⁺: m/z=431.9; found 431.9.

Step 6. 1-(tert-Butyl) 3-methyl(3R,6R)-4-(6-bromo-1-methyl-3-nitro-2-oxo-1,2-dihydro-1,5-naphthyridin-4yl)-6-methylpiperazine-1,3-dicarboxylate

To a mixture of6-bromo-1-methyl-3-nitro-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yltrifluoromethanesulfonate in CH₃CN (3.0 mL) was added 1-(tert-butyl)3-methyl (3R,6R)-6-methylpiperazine-1,3-dicarboxylate (115 mg, 0.44mmol, Ambeed A1152532) followed by dropwise addition ofN-ethyl-N-isopropylpropan-2-amine (0.11 mL, 0.82 mmol), and the reactionmixture was stirred at rt for 1 h. The reaction mixture was concentratedin vacuo and purified by flash column chromatography (12 g SiO₂,EtOAc/hexanes) to afford the desired product (220 mg, quantitative yieldover 2 steps) as a yellow powder. LC-MS calculated for C₂₁H₂₇BrN₅O₇(M+H)⁺: m/z=540.1; found 540.2.

Step 7. tert-Butyl(8aR,1R)-2-bromo-5,11-dimethyl-6,8-dioxo-5,6,7,8,8a,9,11,12-octahydro-10H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-10-carboxylate

To a stirred mixture of 1-(tert-butyl) 3-methyl(3R,6R)-4-(6-bromo-1-methyl-3-nitro-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-6-methylpiperazine-1,3-dicarboxylate(54.0 mg, 0.10 mmol) in AcOH (0.75 mL) was added iron powder (22.3 mg,0.40 mmol) and the reaction mixture was heated to 80° C. for 1 h. Aftercooling to rt, the reaction mixture was concentrated under reducedpressure to give a brown solid. The solid was suspended in CH₂Cl₂ (30mL), and sat. aq. NaHCO₃ was added until the aqueous layer was adjustedto pH ≥8. The mixture was filtered through a pad of Celite and thefilter cake was washed with CH₂Cl₂. After phase separation the organiclayer was removed and the aqueous layer was extracted with CH₂Cl₂. Thecombined organic phases were washed with brine, filtered through a padof celite, dried over Na₂SO₄, and concentrated to give the desiredproduct as brown solid. The crude material obtained was used directlywithout further purification. LC-MS calculated for C₂₀H₂₅BrN₅O₄ (M+H)⁺:m/z=478.1; found 478.2.

Step 8. tert-Butyl(8aR,11R)-2-bromo-5,7,11-trimethyl-6,8-dioxo-5,6,7,8,8a,9,11,12-octahydro-10H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-10-carboxylate

A mixture of tert-butyl(8aR,11R)-2-bromo-5,11-dimethyl-6,8-dioxo-5,6,7,8,8a,9,11,12-octahydro-10H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-10-carboxylatein DMF (0.25 mL) was cooled in an ice-bath before NaH (60% dispersion inmineral oil, 5.0 mg, 0.12 mmol) was added and the reaction mixture wasstirred at rt for 10 mins before methyl iodide (21.1 mg, 0.15 mmol) wasadded dropwise. The ice-bath was removed and the reaction mixture warmedto rt and stirred for an additional 30 mins. The reaction was quenchedby slow addition of water and the mixture was extracted with EtOAc. Thecombined organic phases were washed three times with brine, dried overNa₂SO₄, and concentrated. The crude residue was purified by flash columnchromatography (4 g SiO₂, EtOAc/hexanes) to afford the desired product(39 mg, 79% yield over 2 steps). LC-MS calculated for C₂₁H₂₇BrN₅O₄(M+H)⁺: m/z=492.1; found 492.2.

Step 9.(8aR,11R)-2-Bromo-5,7,11-trimethyl-5,7,9,10,11,12-hexahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-6,8(8aH)-dionehydrochloride

To a mixture of tert-butyl(8aR,11R)-2-bromo-5,7,11-trimethyl-6,8-dioxo-5,6,7,8,8a,9,11,12-octahydro-10H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-10-carboxylatein 1,4-dioxane (0.25 mL) was added a 4 M solution of HCl in 1,4-dioxane(0.25 mL, 1.0 mmol) dropwise and the reaction mixture was stirred at 60°C. for 2 h. After cooling to rt, the reaction mixture was concentratedin vacuo and the solid residue was triturated with a mixture of Et₂O andhexanes. The solid precipitate was allowed to settle, and thesupernatant solvent was decanted off and the residual solid dried undervacuum to provide the desired product as gray powder. The crude materialobtained was used directly without further purification. LC-MScalculated for C₁₆H₁₉BrN₅O₂ (M+H)⁺: m/z=392.1; found 392.1.

Step 10.(8aR,11R)-10-(Bis(4-fluorophenyl)methyl)-2-bromo-5,7,11-trimethyl-5,7,9,10,11,12-hexahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-6,8(8aH)-dione

To a mixture of(8aR,11R)-2-bromo-5,7,11-trimethyl-5,7,9,10,11,12-hexahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-6,8(8aH)-dionehydrochloride (Step 9) in CH₃CN (0.75 mL) was addedN-ethyl-N-isopropylpropan-2-amine (52.4 μL, 0.30 mmol) and the reactionmixture was stirred at rt for 5 mins before4,4′-(chloromethylene)bis(fluorobenzene) (23.9 mg, 0.10 mmol) was addedand the reaction mixture was stirred at 80° C. overnight. After coolingto rt, the reaction mixture was concentrated in vacuo and the cruderesidue as purified by flash column chromatography (4 g SiO₂,EtOAc/hexanes) to give the desired product as yellow foamy solid. LC-MScalculated for C₂₉H₂₇BrF₂N₅O₂ (M+H)⁺: m/z=594.1; found 594.2.

Example 1.(8aR,11R)-10-(Bis(4-fluorophenyl)methyl)-5,7,11-trimethyl-6,8-dioxo-5,7,8,8a,9,10,11,12-octahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-2-carbonitrile

To a mixture of(8aR,11R)-10-(bis(4-fluorophenyl)methyl)-5,11-dimethyl-6,8-dioxo-5,7,8,8a,9,10,11,12-octahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-2-carbonitrile(Intermediate 3, 26.5 mg, 0.050 mmol) in DMF (0.25 mL) was added sodiumhydride (60% dispersion in mineral oil, 10 mg, 0.25 mmol) and themixture was stirred at rt for 5 min before methyl iodide (12 mg, 0.10mmol) was added and the mixture was stirred at rt for 4 h. The reactionwas quenched via the dropwise addition of sat. aq. NH₄Cl prior todiluting with acetonitrile, water, and several drops of TFA. Theresulting mixture was filtered and purified by preparative HPLC (SunfireC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min) to afford the desired product asits TFA salt. LC-MS calculated for C₃₀H₂₇F₂N₆O₂ (M+H)+: m/z=541.2; found541.2.

Example 2.(8aR,11R)-10-(Bis(4-fluorophenyl)methyl)-7-(2-methoxyethyl)-5,11-dimethyl-6,8-dioxo-5,7,8,8a,9,10,11,12-octahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-2-carbonitrile

The title compound was prepared according to the procedures described inExample 1, with 1-iodo-2-methoxyethane replacing methyl iodide. LC-MScalculated for C₃₂H₃₁F₂N₆O₃ (M+H)+: m/z=585.2; found 585.3.

Example 3.(2R,4aR)-3-(Bis(4-fluorophenyl)methyl)-2,6,8-trimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinoline-5,7-dione

Step 1. 4-Hydroxy-1-methyl-3-nitroquinolin-2(1H)-one

A mixture of 4-hydroxy-1-methylquinolin-2(1H)-one (1.75 g, 10.0 mmol) innitric acid (6.0 mL) was stirred at rt for 10 min before the reactionmixture was heated to 75° C. for 15 min. After cooling to rt, ice-waterwas added to the reaction mixture to precipitate the product. The yellowsolid precipitate that formed was collected via filtration and, washedwith ice-water and cold ethanol, and dried under vacuum to obtain thedesired product (1.50 g, 68% yield) as yellow solid. LC-MS calculatedfor C₁₀H₉N₂O₄ (M+H)⁺: m/z=221.2; found 221.1.

Step 2. 4-Chloro-1-methyl-3-nitroquinolin-2(1H)-one

A mixture of 4-hydroxy-1-methyl-3-nitroquinolin-2(1H)-one (200 mg, 0.91mmol) in POCl₃ (1.0 mL, 10.7 mmol) was stirred at 100° C. overnight.After cooling to rt, the reaction mixture was concentrated under reducedpressure to remove excess POCl₃, diluted with water and extracted withEtOAc. The combined organic phases were washed with sat. aq. Na₂CO₃ andbrine, dried over Na₂SO₄, and concentrated to afford the desired product(100 mg, 46% yield) as pale yellow solid. The crude material obtainedwas used directly without further purification. LC-MS calculated forC₁₀H₈ClN₂O₃ (M+H)⁺: m/z=239.2; found 239.1.

Step 3. 1-(tert-Butyl) 3-methyl(3R,6R)-6-methyl-4-(I-methyl-3-nitro-2-oxo-1,2-dihydroquinolin-4-yl)piperazine-1,3-dicarboxylate

To a mixture of 1-(tert-butyl) 3-methyl(3R,6R)-6-methylpiperazine-1,3-dicarboxylate (258 mg, 1.00 mmol) and4-chloro-1-methyl-3-nitroquinolin-2(1H)-one (119 mg, 0.50 mmol) in CH₃CN(2.5 mL) was added N-ethyl-N-isopropylpropan-2-amine (65 mg, 0.50 mmol)and the reaction mixture was stirred at 110° C. overnight. After coolingto rt, the reaction mixture was concentrated in vacuo and the cruderesidue was purified by flash column chromatography (10 g SiO₂,EtOAc/hexanes) to afford the desired product (180 mg, 78% yield) as palegray oil. LC-MS calculated for C₂₂H₂₉N₄O₇ (M+H)⁺: m/z=461.2; found461.1.

Step 4. tert-Butyl(2R,4aR)-2,8-dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinoline-3-carboxylate

To a mixture of 1-(tert-butyl) 3-methyl(3R,6R)-6-methyl-4-(1-methyl-3-nitro-2-oxo-1,2-dihydroquinolin-4-yl)piperazine-1,3-dicarboxylate(180 mg, 0.39 mmol) in MeOH (6.0 mL) was added Pd/C (10 wt %, 30 mg,0.03 mmol) and the reaction mixture was sparged with H₂ gas and stirredunder H₂ (1 atm) for 3 h. LC-MS indicated full conversion. The reactionmixture was filtered through a pad of celite and the filter cake wasrinsed with EtOAc. The filtrate was concentrated to afford the desiredproduct (130 mg, 83% yield) as off-white powder. LC-MS calculated forC₂₁H₂₇N₄O₄ (M+H)⁺: m/z=399.2; found 399.1.

Step 5.(2R,4aR)-2,8-Dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinoline-5,7-dionehydrochloride

To a mixture of tert-butyl(2R,4aR)-2,8-dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinoline-3-carboxylate(60.0 mg, 0.15 mmol) was added a 4 molar solution of HCl (0.4 mL, 1.6mmol) in 1,4-dioxane and the resulting mixture was stirred at 60° C. for1 h. LC-MS indicated full conversion. After cooling to rt, the solventwas removed in vacuo and the solid residue was triturated with a mixtureof Et₂O and hexanes. The solid precipitate was allowed to settle, thesupernatant solvent was decanted off and the residual solid dried undervacuum. The crude material obtained was used directly without furtherpurification. LC-MS calculated for C₁₆H₁₉N₄O₂ (M+H)⁺: m/z=299.1; found299.2.

Step 6.(2R,4aR)-3-(Bis(4-fluorophenyl)methyl)-2,8-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinoline-5,7-dione

To a mixture of(2R,4aR)-2,8-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinoline-5,7-dionehydrochloride (33.5 mg, 0.10 mmol) and N-ethyl-N-isopropylpropan-2-amine(0.052 mL, 0.30 mmol) in CH₃CN (2.5 mL) was added4,4′-(chloromethylene)bis(fluorobenzene) (28.5 mg, 0.12 mmol) and thereaction mixture was stirred at 110° C. overnight. After cooling to rt,the reaction mixture was concentrated in vacuo and the crude residue waspurified using flash column chromatography (4 g SiO₂, EtOAc/hexanes) toafford the desired product (30 mg, 60% yield) as white powder. LC-MScalculated for C₂₉H₂₇F₂N₄O₂ (M+H)⁺: m/z=501.2; found 501.1.

Step 7.(2R,4aR)-3-(Bis(4-fluorophenyl)methyl)-2,6,8-trimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinoline-5,7-dione

To a mixture of(2R,4aR)-3-(bis(4-fluorophenyl)methyl)-2,8-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinoline-5,7-dione(10 mg, 0.020 mmol) in DMF (0.2 mL) was added NaH (60% dispersion inmineral oil, 1.0 mg, 0.025 mmol) and the reaction mixture was stirred atrt for 5 mins before methyl iodide (5.0 mg, 0.05 mmol) was added and themixture was stirred at rt for an additional 2 h. LC-MS indicated fullconversion. The reaction mixture was quenched via the dropwise additionof water prior to diluting with acetonitrile, water, and several dropsof TFA. The resulting mixture was filtered and purified by preparativeHPLC (Sunfire C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min) to afford the desiredproduct as its TFA salt. LC-MS calculated for C₃₀H₂₉F₂N₄O₂ (M+H)+:m/z=515.2; found 515.2.

Example 4.(8aR,11R)-10-(Bis(4-fluorophenyl)methyl)-2-fluoro-5,7,11-trimethyl-5,7,9,10,11,12-hexahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-6,8(8aH)-dione

To a mixture of(8aR,11R)-10-(bis(4-fluorophenyl)methyl)-2-bromo-5,7,11-trimethyl-5,7,9,10,11,12-hexahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-6,8(8aH)-dione(Intermediate 4, 15 mg, 0.025 mmol) in DMSO (0.3 mL) was added cesiumfluoride (11.5 mg, 0.076 mmol) and the reaction mixture was flushed withN₂ and stirred at 130° C. for 1 h. After cooling to rt, the mixture wasdiluted with acetonitrile, water, and several drops of TFA. Theresulting mixture was filtered and purified by preparative HPLC (SunfireC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min) to afford the desired product asits TFA salt. LC-MS calculated for C₂₉H₂₇F₃N₅O₂ (M+H)⁺: m/z=534.2; found534.4.

Example 5.(8aR,11R)-10-(Bis(4-fluorophenyl)methyl)-2,5,7,11-tetramethyl-5,7,9,10,11,12-hexahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-6,8(8aH)-dione

To a mixture of(8aR,11R)-10-(bis(4-fluorophenyl)methyl)-2-bromo-5,7,11-trimethyl-5,7,9,10,11,12-hexahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-6,8(8aH)-dione(Intermediate 4, 15 mg, 0.025 mmol),2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (9.5 mg, 0.076 mmol) andpotassium carbonate (10.5 mg, 0.076 mmol) in 1,4-dioxane (0.3 mL) wasadded [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (2.1 mg, 2.6 μmol) and the reaction mixturewas flushed with N₂ and stirred at 100° C. overnight. After cooling tort, the mixture was diluted with acetonitrile, water, and several dropsof TFA. The resulting mixture was filtered and purified by preparativeHPLC (Sunfire C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min) to afford the desiredproduct as its TFA salt. LC-MS calculated for C₃₀H₃₀F₂N₅O₂ (M+H)⁺:m/z=530.2; found 530.3.

Example 6.2-((8aR,11R)-10-(Bis(4-fluorophenyl)methyl)-5,7,11-trimethyl-6,8-dioxo-5,7,8,8a,9,10,11,12-octahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridin-2-yl)acetonitrile

To a mixture of(8aR,11R)-10-(bis(4-fluorophenyl)methyl)-2-bromo-5,7,11-trimethyl-5,7,9,10,11,12-hexahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-6,8(8aH)-dione(Intermediate 4, 15 mg, 0.025 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (14.8 mg, 0.076mmol) and potassium fluoride (4.4 mg, 0.076 mmol) in DMSO (0.3 mL) wasadded [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (2.1 mg, 2.6 μmol) and water (1.4 mg, 0.08mmol) and the reaction mixture was flushed with N₂ and stirred at 130°C. overnight. After cooling to rt, the mixture was diluted withacetonitrile, water, and several drops of TFA. The resulting mixture wasfiltered and purified by preparative HPLC (Sunfire C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% TFA, at flow rateof 60 mL/min) to afford the desired product as its TFA salt. LC-MScalculated for C₃₁H₂₉F₂N₆O₂(M+H)⁺: m/z=555.2; found 555.3.

Example 7.(8aR,11R)-10-(Bis(4-fluorophenyl)methyl)-2-methoxy-5,7,11-trimethyl-5,7,9,10,11,12-hexahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-6,8(8aH)-dione

To a mixture of(8aR,11R)-10-(bis(4-fluorophenyl)methyl)-2-bromo-5,7,11-trimethyl-5,7,9,10,11,12-hexahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-6,8(8aH)-dione(Intermediate 4, 15 mg, 0.025 mmol) in MeOH (0.3 mL) was added a 5 Msolution of sodium methoxide in MeOH (50.5 μl, 0.252 mmol) dropwise andthe reaction was stirred at 80° C. overnight. After cooling to rt, themixture was diluted with acetonitrile, water, and several drops of TFA.The resulting mixture was filtered and purified by preparative HPLC(Sunfire C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min) to afford the desiredproduct as its TFA salt. LC-MS calculated for C₃₀H₃₀F₂N₅O₃ (M+H)⁺:m/z=546.2; found 546.3.

Example 8.(8aR,11R)-10-(Bis(4-fluorophenyl)methyl)-5,7,11-trimethyl-2-(1-methyl-1H-pyrazol-4-yl)-5,7,9,10,11,12-hexahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-6,8(8aH)-dione

To a mixture of(8aR,11R)-10-(bis(4-fluorophenyl)methyl)-2-bromo-5,7,11-trimethyl-5,7,9,10,11,12-hexahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-6,8(8aH)-dione(Intermediate 4, 15 mg, 0.025 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(15.75 mg, 0.076 mmol) and potassium carbonate (10.46 mg, 0.076 mmol) in1,4-dioxane (0.3 mL) and water (0.1 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (2.1 mg, 2.6 μmol) and the reaction mixture thenflushed with N₂ and stirred at 100° C. overnight. After cooling to rt,the mixture was diluted with acetonitrile, water, and several drops ofTFA. The resulting mixture was filtered and purified by preparative HPLC(Sunfire C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min) to afford the desiredproduct as its TFA salt. LC-MS calculated for C₃₃H₃₂F₂N₇O₂(M+H)⁺:m/z=596.2; found 596.4.

Example 9.(8aR,11R)-10-(Bis(4-fluorophenyl)methyl)-5,7,11-trimethyl-5,7,9,10,11,12-hexahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-2,6,8(8aH)-trione

A mixture of(8aR,11R)-10-(bis(4-fluorophenyl)methyl)-2-bromo-5,7,11-trimethyl-5,7,9,10,11,12-hexahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-6,8(8aH)-dione(Intermediate 4, 15 mg, 0.025 mmol),methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(2.1 mg, 2.3 μmol), KOH (4.2 mg, 0.075 mmol) and H₂O (9 μL, 0.5 mmol) in1,4-dioxane was stirred at 80° C. for 2 h. After cooling to rt, themixture was diluted with acetonitrile, water, and several drops of TFA.The resulting mixture was filtered and purified by preparative HPLC(Sunfire C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min) to afford the desiredproduct as its TFA salt. LC-MS calculated for C₂₉H₂₈F₂N₅O₃ (M+H)⁺:m/z=532.2; found 532.3.

Example A. In Vitro DGKα and DGKζ Inhibition Assays

The DGKα and DGKζ biochemical reactions were performed using His-taggedhuman recombinant enzymes (Signal Chem, DGKα, #D21-10BH; DGKζ,#D30-10H)) and DLG (Dilauroyl-sn-glycerol) lipid substrate (Signal Chem,#D430-59). ADP-Glo assay was performed using ADP-Glom kinase Assay kit(Promega, #V9104). The reactions were carried out in assay buffercontaining 40 mM Tris, pH 7.5, 0.1% CHAPS, 0.1% Prionex, 40 mM NaCl, 5mM MgCl₂, 1 mM CaCl₂), and 1 mM DTT. DGKα reactions contained 0.1 nMDGKα, 50 μM ATP, and 20 μM DLG. And DGKζ reactions contained 0.4 nMDGKζ, 30 μM ATP, and 20 μM DLG.

For compound inhibition studies, 40 nL test compound in DMSO was addedto wells of white polystyrene plates in 384-well (Greiner, #784075) or1536-well format (Greiner, #782075). Compounds were added with topconcentration of 2 mM with 11 point, 3-fold dilution series. Enzymesolution (contains 2×DGK enzyme concentration in 1× assay buffer) wasadded to the plate in 2 μL/well volume, followed by 2 μL/well ofsubstrate solution (contains 2× concentration of ATP and DLG substratein 1× assay buffer). Plates were then centrifuged for 1 min at 1200 RPMand sealed or lidded. For 4 μL reaction volume, test compounds weretherefore diluted 100× to final top concentration of 20 μM. After 90minute incubation, reactions were quenched by addition of 2 μL/wellPromega ADP-Glo Reagent, followed by centrifugation and lidding. After60 min incubation, 2 μL/well Promega Kinase Detection Reagent was added,plates centrifuged, and incubated for 30 min. Plates were then readusing Luminescence method on BMG PHERAstar FSX plate reader. Percentinhibition was calculated and IC₅₀s were determined using 4-parameterfit in Genedata Screener. Labcyte Echo acoustic dispenser was used forcompound addition, and Formulatrix Tempest liquid handler was used forall reagent dispenses.

The compounds of the disclosure were tested in one or more of the assaysdescribed in Example A, and the resulting data are shown in Table A.

TABLE A Example DGKα IC₅₀ (nM) DGKζ IC₅₀ (nM) 1 + +++ 2 ++ +++ 3 + ++++4 + +++ 5 + ++++ 6 + + 7 + ++++ 8 + ++++ 9 + ++++ + refers to IC₅₀ of≤40 nM ++ refers to IC₅₀ of >40 nM to ≤200 nM +++ refers to IC₅₀ of >200nM to ≤2000 nM ++++ refers to IC₅₀ of >2000 nM

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

is a single or double bond; W is CR⁷, C(O), N, or NR⁷; X is CR⁸, C(O),N, or NR⁸; Y is CR⁹ or N; Z is CR¹⁰ or N; wherein no more than 2 of W,X, Y, and Z can be N or a substituted N; n is 0, 1, or 2; each R² isindependently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl,4-7 membered heterocycloalkyl, CN, NO₂, OR^(a2), NHOR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)NR^(c2)(OR^(a2)), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)NR^(c2)R^(d2),NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2),C(═NR^(e2))R^(b2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(c2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))R^(b2),NR^(c2)S(O)R^(b2), NR^(c2)S(O)NR^(c2)R^(d2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)(═NR^(e2))R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), S(O)₂NR^(c2)R^(d),OS(O)(═NR^(e2))R^(b2), and OS(O)₂R^(b2), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl of R² are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents; eachR^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-; or, any R^(c2) and R^(d2)attached to the same N atom, together with the N atom to which they areattached, form a 5-6 membered heteroaryl or a 4-7 memberedheterocycloalkyl group; each R^(b2) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-; each R^(e2) is independently selected from H, OH, CN, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-; R³ is selected from H, halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, and 4-7 membered heterocycloalkyl-, wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, and 4-7 membered heterocycloalkyl of R³ are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(M)substituents; R⁵ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl of R⁵ are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents; R⁷ isselected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, —C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a7), SR^(a7),NHOR^(c7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)NR^(c7)(OR^(a7)),C(O)OR^(a7), OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7),NR^(c7)NR^(c7)R^(d7) NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7),NR^(c7)C(O)NR^(c7)R^(d7), C(═NR^(e7))R^(b7), C(═NR^(e7))NR^(c7)R^(d7),C(═NOR^(e7))R^(b7), C(═NOR^(a7))OR^(a7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)C(═NR^(e7))R^(b7),NR^(c7)S(O)R^(b7), NR^(c7)S(O)NR^(c7)R^(d7), NR^(c7)S(O)₂R^(b7),NR^(c7)S(O)(═NR^(e7))R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7),S(O)NR^(c7)R^(d7), S(O)₂R^(b7), S(O)₂NR^(c7)R^(d7),OS(O)(═NR^(e7))R^(b7), and OS(O)₂R^(b7), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R⁷ are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(7A) substituents; each R^(a7), R^(c7), and R^(d7) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a7), R^(c7) andR^(d7) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(7A) substituents; or, any R^(c7) and R^(d7)attached to the same N atom, together with the N atom to which they areattached, form a 5-10 membered heteroaryl or a 4-10 memberedheterocycloalkyl group, wherein the 5-10 membered heteroaryl or 4-10membered heterocycloalkyl group is optionally substituted with 1, 2, 3,4, 5, 6, 7, or 8 independently selected R^(7A) substituents; each R^(b7)is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R⁷ are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(7A) substituents; each R^(e7) is independently selected fromH, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-; each R^(7A) isindependently selected from halo, oxo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a71),SR^(a71), NHOR^(a71), C(O)R^(b71), C(O)NR^(c71)R^(d71),C(O)NR^(c71)(OR^(a71)), C(O)OR^(a71), OC(O)R^(b71),OC(O)NR^(c71)R^(d71), NR^(c71)R^(d71), NR^(c71)NR^(c71)R^(d71),NR^(c71)C(O)R^(b71), NR^(c71)C(O)OR^(a71), NR^(c71)C(O)NR^(c71)R^(d71),C(═NR^(e71))R^(b71), C(═NR^(e71))NR^(c71)R^(d71), C(═NOR^(e71))R^(b71),C(═NOR^(e71))OR^(a71), NR^(c71)C(═NR⁷¹)NR^(c71)R^(d71),NR^(c71)C(═NR^(e71))R^(b71), NR^(c71)S(O)R^(b71),NR^(c71)S(O)NR^(c71)R^(d71), NR^(c71)S(O)₂R^(b71),NR^(c71)S(O)(═NR^(e71))R^(b71), NR^(c71)S(O)₂NR^(c71)R^(d71),S(O)R^(b71), S(O)NR^(c71)R^(d71), S(O)₂R^(b71), S(O)₂NR^(c71)R^(d71),OS(O)(═NR^(c71))R^(b71), and OS(O)₂R^(b71), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(7A) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(M) substituents; each R^(a71), R^(c71), and R^(d71) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a71), R^(c71) andR^(d71) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(M) substituents; or, any R^(c71) and R^(d71)attached to the same N atom, together with the N atom to which they areattached, form a 5-10 membered heteroaryl or a 4-10 memberedheterocycloalkyl group, wherein the 5-10 membered heteroaryl or 4-10membered heterocycloalkyl group is optionally substituted with 1, 2, 3,4, 5, 6, 7, or 8 independently selected R^(M) substituents; each R^(b71)is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R⁷¹ are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(M) substituents; each R^(e71) is independently selected fromH, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-; R⁸ is selected from H,halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, —C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a8), SR^(a8), NHOR^(a8),C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)NR^(c8)(OR^(a8)), C(O)OR^(a8),OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)NR^(c8)R^(d8),NR^(c8)C(O)R^(b8), NR^(c8)C(O)OR^(a8), NR^(c8)C(O)NR^(c8)R^(d8),C(═NR^(e8))R^(b8), C(═NR^(e8))NR^(c8)R^(d8), C(═NOR^(e8))R^(b8),C(═NOR^(a8))OR^(a8), NR^(c8)C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))R^(b8), NR^(c8)S(O)R^(b8), NR^(c8)S(O)NR^(c8)R^(d8),NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)(═NR^(e8))R^(b8),NR^(c8)S(O)₂NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8), S(O)₂R^(b8),S(O)₂NR^(c8)R^(d8), OS(O)(═NR^(e8))R^(b8), and OS(O)₂R^(b8), wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R⁸ are each optionally substituted with 1, 2, 3, 4, 5, 6, 7,or 8 independently selected R^(8A) substituents; each R^(B), R^(c8), andR^(d8) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a8),R^(c8) and R^(d8) are each optionally substituted with 1, 2, 3, 4, 5, 6,7, or 8 independently selected R^(8A) substituents; or, any R^(c8) andR^(d8) attached to the same N atom, together with the N atom to whichthey are attached, form a 5-10 membered heteroaryl or a 4-10 memberedheterocycloalkyl group, wherein the 5-10 membered heteroaryl or 4-10membered heterocycloalkyl group is optionally substituted with 1, 2, 3,4, 5, 6, 7, or 8 independently selected R^(8A) substituents; each R^(b8)is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b8) areeach optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(8A) substituents; each R^(c8) is independently selected fromH, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-; each R^(8A) isindependently selected from halo, oxo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a81),SR^(a81), NHOR^(a81), C(O)R^(b81), C(O)NR^(c81)R^(d81),C(O)NR^(c81)(OR^(a81)), C(O)OR^(a81), OC(O)R^(b81),OC(O)NR^(c81)R^(d81), NR^(c81)R^(d81), NR^(c81)NR^(c81)R^(d81),NR^(c81)C(O)R^(b81), NR^(c81)C(O)OR^(b81), NR^(c81)C(O)NR^(c81)R^(d81),C(═NR^(e81))R^(b81), C(═NR^(c81))NR^(c81)R^(d81), C(═NOR^(a81))R^(b81),C(═NOR^(a81))OR^(a81), NR^(c81)C(═NR^(e81))NR^(c81)R^(d81),NR^(c81)C(═NR^(e81))R^(b81), NR^(c81)S(O)R^(b81),NR^(c81)S(O)NR^(c81)R^(d81), NR^(c81)S(O)₂R^(b81),NR^(c81)S(O)(═NR^(e81))R^(b81), NR^(c81)S(O)₂NR^(c81)R^(d81),S(O)R^(b81), S(O)NR^(c81)R^(d81), S(O)₂R^(b81), S(O)₂NR^(c81)R^(d81),OS(O)(═NR^(e81))R^(b81), and OS(O)₂R^(b81), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(8A) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(M) substituents; each R^(a81), R^(c81), and R^(d81) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a81), R^(c81) andR^(d81) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(M) substituents; or, any R^(c81) and R^(d81)attached to the same N atom, together with the N atom to which they areattached, form a 5-10 membered heteroaryl or a 4-10 memberedheterocycloalkyl group, wherein the 5-10 membered heteroaryl or 4-10membered heterocycloalkyl group is optionally substituted with 1, 2, 3,4, 5, 6, 7, or 8 independently selected R^(M) substituents; each R^(b81)is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b81) areeach optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(M) substituents; each R^(e81) is independently selected fromH, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-; R⁹ is selected from H,halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a9), SR^(c9), NHOR^(a9), C(O)R^(b9), C(O)NR^(c9)R^(d9),C(O)NR^(c9)(OR^(a9)), C(O)OR^(a9), OC(O)R^(b9), OC(O)NR^(c9)R^(d9),NR^(c99)R^(d99), NR^(c9)NR^(c9)R^(d9), NR^(c9)(O)R^(b9),NR^(c9)C(O)OR^(a9), NR^(c9)C(O)NR^(c9)R^(d9), C(═NR^(e9))R^(b9),C(═NR^(e9))NR^(c9)R^(d9), C(═NOR^(a9))R^(b9), C(═NOR^(a9))OR^(a9),NR^(c9)C(═NR^(e9))NR^(c9)R^(d9), NR^(c9)(═NR^(e9))R^(b9),NR^(c9)S(O)R^(b9), NR^(c9)S(O)NR^(c9)R^(d9), NR^(c9)S(O)₂R^(b9),NR^(c9)(O)(═NR^(e9))R^(b9), NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)R^(b9),S(O)NR^(c9)R^(d9), S(O)₂R^(b9), S(O)₂NR^(c9)R^(d9), OS(O)(═NR⁹)R^(b9),and OS(O)₂R^(b9), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R⁹ are each optionally substituted with 1, 2, 3, 4, 5, 6, 7,or 8 independently selected R^(9A) substituents; each R^(a9), R^(c9),and R^(d9) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a9),R^(c9) and R^(d9) are each optionally substituted with 1, 2, 3, 4, 5, 6,7, or 8 independently selected R^(9A) substituents; or, any R^(c9) andR^(d9) attached to the same N atom, together with the N atom to whichthey are attached, form a 5-10 membered heteroaryl or a 4-10 memberedheterocycloalkyl group, wherein the 5-10 membered heteroaryl or 4-10membered heterocycloalkyl group is optionally substituted with 1, 2, 3,4, 5, 6, 7, or 8 independently selected R^(9A) substituents; each R^(c9)and R^(d9) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a9), R^(c9) and R^(d9) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(9A) substituents; each R^(b9) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R⁹ are each optionallysubstituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(9A)substituents; each R⁹ is independently selected from H, OH, CN, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-; each R^(9A) is independently selectedfrom halo, oxo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a91), SR^(a91), NHOR^(a91),C(O)R^(b91), C(O)NR^(c91)R^(d91), C(O)NR^(c91)(OR^(a91)), C(O)OR^(a91),OC(O)R^(b91), OC(O)NR^(c91)R^(d91), NR^(c91)R^(d91),NR^(c91)NR^(c91)R^(d91), NR^(c91)C(O)R^(b91), NR^(c91)C(O)OR^(a91),NR^(c91)C(O)NR^(c91)R^(d91), C(═NR^(e91))R^(b91),C(═NR^(e91))NR^(c91)R^(d91), C(═NOR^(a91))R^(b91),C(═NOR^(a91))OR^(a91), NR^(c91)C(═NR^(e91))NR^(c91)R^(d91),NR^(c91)C(═NR^(e91))R^(b91), NR^(c91)S(O)R^(b91),NR^(c91)S(O)NR^(c91)R^(d91), NR^(c91)S(O)₂R^(c91),NR^(c91)S(O)(═NR^(e91))R^(c91), NR^(c91)S(O)₂NR^(c91)R^(d91),S(O)R^(b91), S(O)NR^(c91)R^(d91), S(O)₂R^(b91), S(O)₂NR^(c91)R^(d91),OS(O)(═NR^(e91))R^(b91), and OS(O)₂R^(b91), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(9A) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(M) substituents; each R^(a91), R^(c91), and R^(d91) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a91), R^(c91) andR^(d91) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(M) substituents; or, any R^(c91) and R^(d91)attached to the same N atom, together with the N atom to which they areattached, form a 5-10 membered heteroaryl or a 4-10 memberedheterocycloalkyl group, wherein the 5-10 membered heteroaryl or 4-10membered heterocycloalkyl group is optionally substituted with 1, 2, 3,4, 5, 6, 7, or 8 independently selected R^(M) substituents; each R^(b91)is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b91) areeach optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(M) substituents; each R^(e91) is independently selected fromH, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-; R¹⁰ is selected fromH, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a10), SR^(a10), NHOR^(a10),C(O)R^(b10), C(O)NR^(c10)R^(d10), C(O)NR^(c10)(OR^(a10)), C(O)OR^(a10),OC(O)R^(b10), OC(O)NR^(c10)R^(d10), NR^(c10)R^(d10),NR^(c10)NR^(c10)R^(d10), NR^(c10)C(O)R^(b10), NR^(c10)C(O)OR^(a10),NR^(c10)C(O)NR^(c10)R^(d10), C(═NR^(c10))R^(b10),C(═NR^(c10))NR^(c10)R^(d10), C(═NOR^(a10))R^(b10),C(═NOR^(a10))OR^(a10), NR^(c10)C(═NR^(c10))NR^(c10)R^(d10),NR^(c10)C(═NR^(c10))R^(b10), NR^(c10)S(O)R^(b10),NR^(c10)S(O)NR^(c10)R^(d10), NR^(c10)S(O)₂R^(b10),NR^(c10)S(O)(═NR^(e10))R^(b10), NR^(c10)S(O)NR^(c10)R^(d10),S(O)R^(b10), S(O)NR^(c10)R^(d10), S(O)₂R^(b10), S(O)₂NR^(c10)R^(d10),OS(O)(═NR^(c10))R^(b10), and OS(O)₂R^(b10), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R¹⁰ are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(10A) substituents; each R^(a10), R^(c10), and R^(d10) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a10), R^(c10) andR^(d10) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(10A) substituents; or, any R^(c10) and R^(d10)attached to the same N atom, together with the N atom to which they areattached, form a 5-10 membered heteroaryl or a 4-10 memberedheterocycloalkyl group, wherein the 5-10 membered heteroaryl or 4-10membered heterocycloalkyl group is optionally substituted with 1, 2, 3,4, 5, 6, 7, or 8 independently selected R^(10A) substituents; eachR^(b10) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b10) areeach optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(10A) substituents; each R¹⁰ is independently selected fromH, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-; each R^(10A) isindependently selected from halo, oxo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a101),SR^(a101), NHOR^(a101), C(O)R^(b101), C(O)NR^(c101)R^(d101),C(O)NR^(c101)(OR^(a101)), C(O)OR^(a101), OC(O)R^(b101),OC(O)NR^(c101)R^(d101), NR^(c101)R^(d101), NR^(c101)NR^(c101)R^(d101),NR^(c101)C(O)R^(b101), NR^(c101)C(O)OR^(a101),NR^(c101)C(O)NR^(c101)R^(d101), C(═NR^(c101))R^(b101),C(═NR^(e101))NR^(c101)R^(d101), C(═NOR^(a101))R^(b101),C(═NOR^(a101))OR^(a101), NR^(c101)C(═NR^(e101))NR^(c101)R^(d101),NR^(c101)C(═NR^(e101))R^(b101), NR^(c101)S(O)R^(b101),NR^(c101)S(O)NR^(c101)R^(d101), NR^(c101)S(O)₂R^(b101),NR^(c101)S(O)(═NR^(e101))R^(b101), NR^(c101)S(O)₂NR^(c101)R^(d101),S(O)R^(b101), S(O)NR^(c101)R^(d101), S(O)₂R^(b101),S(O)₂NR^(c101)R^(d101), OS(O)(═NR^(e101))R^(b101), and OS(O)₂R^(b101),wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R^(10A) are each optionally substituted with 1, 2, 3, 4, 5, 6,7, or 8 independently selected R^(M) substituents; each R^(a101),R^(c101), and R^(d101) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a101), R^(c101) and R^(d101) areeach optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(M) substituents; or, any R^(c101) and R^(d101) attached tothe same N atom, together with the N atom to which they are attached,form a 5-10 membered heteroaryl or a 4-10 membered heterocycloalkylgroup, wherein the 5-10 membered heteroaryl or 4-10 memberedheterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6,7, or 8 independently selected R^(M) substituents; each R^(b101) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b101) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(M) substituents; each R^(e101) is independently selectedfrom H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-; L¹ is C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₃₋₆ cycloalkyl,or 4-6 membered heterocycloalkyl; Cy¹ is a C₆₋₁₀ aryl or 5-10 memberedheteroaryl, wherein the C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R¹¹ substituents; each R¹¹ is independently selected from halo,oxo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a11), SR^(a11), NHOR^(a11),C(O)R^(b11), C(O)NR^(c11)R^(d11), C(O)NR^(c11)(OR^(a11)), C(O)OR^(a11),OC(O)R^(b11), OC(O)NR^(c11)R^(d11), NR^(c11)R^(d11),NR^(c11)NR^(c11)R^(d11), NR^(c11)C(O)R^(b11), NR^(c11)C(O)OR^(a11),NR^(c11)C(O)NR^(c11)R^(d11), C(═NR^(e11))R^(b11),C(═NR^(e11))NR^(c11)R^(d11), NR^(c11)C(═NR^(e11))NR^(c11)R^(d11),NR^(c11)C(═NR^(e11))R^(b11), NR^(c11)S(O)R^(b11),NR^(c11)S(O)NR^(c11)R^(d11), NR^(c11)S(O)₂R^(b11),NR^(c11)S(O)(═NR^(e11))R^(b11), NR^(c11)S(O)₂NR^(c11)R^(d11),S(O)R^(b11), S(O)NR^(c11)R^(d11), S(O)₂R^(b11), S(O)₂NR^(c11)R^(d11),OS(O)(═NR^(e11))R^(b11), and OS(O)₂R^(b11), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R¹¹ are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(11A) substituents; each R^(a11), R^(c11), and R^(d11) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a11), R^(c11) andR^(d11) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(11A) substituents; or, any R^(c11) and R^(d11)attached to the same N atom, together with the N atom to which they areattached, form a 5-10 membered heteroaryl or a 4-10 memberedheterocycloalkyl group, wherein the 5-10 membered heteroaryl or 4-10membered heterocycloalkyl group is optionally substituted with 1, 2, 3,4, 5, 6, 7, or 8 independently selected R^(11A) substituents; eachR^(b11) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b11) areeach optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(11A) substituents; each R^(e11) is independently selectedfrom H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-; each R^(11A) is independently selected from halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a111),C(O)NR^(c111)R^(d11), C(O)OR^(a111), NR^(c111)R^(d111),S(O)NR^(c111)R^(d111), S(O)₂R^(b111), S(O)₂NR^(c111)R^(d111), andOS(O)₂R^(b111), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-, of R^(11A) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents; each R^(a111), R^(c111), and R^(d111) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a111), R^(c111) and R^(d111) areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(M) substituents; or, any R^(c111) and R^(d111) attached to the same Natom, together with the N atom to which they are attached, form a 5-6membered heteroaryl or a 4-7 membered heterocycloalkyl group, whereinthe 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(M)substituents; each R^(b111) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-of R^(b111) are each optionally substituted with 1, 2, 3, or 4independently selected R^(M) substituents; R¹² is selected from H, halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a12), SR^(a12), NHOR^(a12),C(O)R^(a12), C(O)NR^(c12)R^(d12), C(O)NR^(c12)(OR^(a12)), C(O)OR^(a12),OC(O)R^(a12), OC(O)NR^(c12)R^(d12), NR^(c12)R^(d12),NR^(c12)NR^(c12)R^(d12), NR^(c12)C(O)R^(b12), NR^(c12)C(O)OR^(a12),NR^(c12)C(O)NR^(c12)R^(d12), C(═NR^(c12))R^(b12),C(═NR^(e12))NR^(c12)R^(d12), NR^(c12)C(═NR^(e12))NR^(c12)R^(d12),NR^(c12)C(═NR^(e12))R^(b12), NR^(c12)S(O)R^(b12),NR^(c12)S(O)NR^(c12)R^(d12), NR^(c12)S(O)₂R^(b12),NR^(c12)S(O)(═NR^(e12))R^(b12), NR^(c12)S(O)₂NR^(c12)R^(d12),S(O)R^(b12), S(O)NR^(c12)R^(d12), S(O)₂R^(b12), S(O)₂NR^(c12)R^(d12),OS(O)(═NR^(e12))R^(b12), and OS(O)₂R^(b12), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R¹² are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(12A) substituents; each R^(a12), R^(c12), and R^(d12) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a12), R^(c12) andR^(d12) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(12A) substituents; or, any R^(c12) and R^(d12)attached to the same N atom, together with the N atom to which they areattached, form a 5-10 membered heteroaryl or a 4-10 memberedheterocycloalkyl group, wherein the 5-10 membered heteroaryl or 4-10membered heterocycloalkyl group is optionally substituted with 1, 2, 3,4, 5, 6, 7, or 8 independently selected R^(12A) substituents; eachR^(b12) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R² are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(12A) substituents; each R^(e12) is independently selectedfrom H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-; each R^(12A) is independently selected from halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a121), SR^(a121), NHOR^(a121), C(O)R^(b121),C(O)NR^(c121)R^(d121), C(O)NR^(c121)(OR^(a121)), C(O)OR^(a121),OC(O)R^(b121), OC(O)NR^(c121)R^(d121), NR^(c121)R^(d121),NR^(c121)NR^(c121)R^(d121), NR^(c121)C(O)R^(b121),NR^(c121)C(O)OR^(a121), NR^(c121)C(O)NR^(c121)R^(d121),C(═NR^(e121))R^(b121), C(═NR^(e121))NR^(c121)R^(d121),NR^(c121)C(═NR^(e121))NR^(c121)R^(d121), NR^(c121)C(═NR^(e121))R^(b121),NR^(c121)S(O)R^(b121), NR^(c121)S(O)NR^(c121)R^(d121),NR^(c121)S(O)₂R^(b121), NR^(c121)S(O)(═NR^(e121))R^(b121),NR^(c121)S(O)₂NR^(c121)R^(d121), S(O)R^(b121), S(O)NR^(c121)R^(d121),S(O)₂R^(b121), S(O)₂NR^(c121)R^(d121), OS(O)(═NR^(e121))R^(b121), andOS(O)₂R^(b121), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(12A) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected Rim substituents;each R^(a121), R^(c121), and R^(d121) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a121), R^(c121) andR^(d121) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(12B) substituents; or, any R^(c121) andR^(d121) attached to the same N atom, together with the N atom to whichthey are attached, form a 5-10 membered heteroaryl or a 4-10 memberedheterocycloalkyl group, wherein the 5-10 membered heteroaryl or 4-10membered heterocycloalkyl group is optionally substituted with 1, 2, 3,4, 5, 6, 7, or 8 independently selected R^(12B) substituents; eachR^(b121) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b121) areeach optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(12B) substituents; each R^(e121) is independently selectedfrom H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-; each R^(12B) is independently selected from halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a122),C(O)NR^(c122)R^(d122), C(O)OR^(a122), NR^(c122)R^(d122),S(O)NR^(c122)R^(d122), S(O)₂R^(b122), S(O)₂NR^(c122)R^(d122), andOS(O)₂R^(b122), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-, of R^(12B) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents; each R^(a122), R^(c122), and R^(d122) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a122), R^(c122) and R^(d122) areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(M) substituents; or, any R^(c122) and R^(d122) attached to the same Natom, together with the N atom to which they are attached, form a 5-6membered heteroaryl or a 4-7 membered heterocycloalkyl group, whereinthe 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(M)substituents; each R¹22 is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b122) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents; and each R^(M) is independently selected from H, OH, halo,oxo, CN, C(O)OH, NH₂, NO₂, SF₅, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-.
 2. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein W is CR⁷, N, or NR⁷.
 3. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein R⁷ is selectedfrom H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl.
 4. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein W is CH, N, or NH.
 5. The compound of claim 1, ora pharmaceutically acceptable salt thereof, wherein X is CR⁸ or C(O). 6.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein X is CR⁸.
 7. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is selected from H, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,—C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, and OR⁸, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁸ are each optionally substituted with1, 2, 3, or 4 independently selected R^(8A) substituents.
 8. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁸ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl,4-7 membered heterocycloalkyl-, CN, and OR⁸, wherein C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, and 4-7 membered heterocycloalkyl- of R⁸ are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(8A)substituents.
 9. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is selected from H, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, 5-6 membered heteroaryl, CN, and OR^(a8), whereinC₁₋₆ alkyl and 5-6 membered heteroaryl of R⁸ are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(8A)substituents; and each R^(a8) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.
 10. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein eachR^(8A) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, and CN.
 11. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein each R^(8A) isindependently selected from C₁₋₆ alkyl and CN.
 12. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R⁸ is selectedfrom H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, 5-6 membered heteroaryl, CN,and OR^(a8), wherein C₁₋₆ alkyl and 5-6 membered heteroaryl of R⁸ areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(8A) substituents independently selected from C₁₋₆ alkyl and CN; andeach R^(a8) is independently selected from H and C₁₋₆ alkyl.
 13. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁸ is selected from H, fluoro, methyl, cyanomethyl, cyano,methoxy, and methylpyrazolyl.
 14. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein X is C(O).
 15. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein Y is CR⁹.
 16. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁹ is selected from H, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.
 17. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein Y isCH.
 18. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein Z is CR¹⁰.
 19. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹⁰ is selected fromH, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl. 20.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein Z is CH.
 21. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein Y and Z are each CH.
 22. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein nis
 1. 23. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein each R² is independently selected from halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.
 24. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein eachR² is independently selected from C₁₋₆ alkyl.
 25. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein each R² ismethyl.
 26. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R³ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.
 27. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein R³ is selectedfrom H and C₁₋₆ alkyl.
 28. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R³ is methyl.
 29. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁵ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl of R⁵ are each optionally substituted with 1, 2, 3, or 4independently selected R^(M) substituents.
 30. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein R⁵ is selectedfrom H and C₁₋₆ alkyl, wherein the C₁₋₆ alkyl of R⁵ is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents.
 31. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein each R^(M) is independently selectedfrom OH, halo, oxo, CN, C(O)OH, NH₂, NO₂, SF₅, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, and C₁₋₆ haloalkyl.
 32. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁵ is selected frommethyl and methoxyethyl.
 33. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein L¹ is C₁₋₃ alkyl. 34.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein L¹ is CH.
 35. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein Cy¹ is phenyl or 5-6 memberedheteroaryl, wherein the phenyl and 5-6 membered heteroaryl of Cy¹ areeach optionally substituted with 1, 2, 3, or 4 independently selected R¹substituents.
 36. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein Cy¹ is phenyl, which is optionallysubstituted with 1, 2, 3, or 4 independently selected R¹¹ substituents.37. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein each R¹¹ is independently selected from halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.
 38. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein eachR¹¹ is independently selected from halo.
 39. The compound of claim 1, ora pharmaceutically acceptable salt thereof, wherein Cy¹ is fluorophenyl.40. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹² is phenyl or 5-6 membered heteroaryl, wherein thephenyl and 5-6 membered heteroaryl of R¹² are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(12A)substituents.
 41. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R¹² is phenyl, which is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(12A)substituents.
 42. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein each R^(12A) is independently selectedfrom halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.43. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein each R^(12A) is independently selected from halo. 44.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R¹² is fluorophenyl.
 45. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Cy¹ and R¹² are eachfluorophenyl.
 46. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein: W is CR⁷, C(O), N, or NR⁷; X is CR⁸,C(O), N, or NR⁸; Y is CH; Z is CH; n is 0, 1, or 2; each R² isindependently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl,4-7 membered heterocycloalkyl, CN, NO₂, OR^(a2), NHOR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)NR^(c2)(OR^(a2)), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)NR^(c2)R^(d2),NR^(c2)C(O)R^(b2), NR^(c2)(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2),C(═NR^(e2))R^(b2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))R^(b2),NR^(c2)S(O)R^(b2), NR^(c2)S(O)NR^(c2)R^(d2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)(═NR^(e2))R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), S(O)₂NR^(c2)R^(d2),OS(O)(═NR^(e2))R^(b2), and OS(O)₂R^(b2); each R^(a2), R^(c2), and R^(d2)is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl,4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-; or, any R^(c2) and R^(d2) attached to thesame N atom, together with the N atom to which they are attached, form a5-6 membered heteroaryl or a 4-7 membered heterocycloalkyl group; eachR^(b2) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-; each R^(e2) is independentlyselected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-; R³ is selected from H,halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl,C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl of R³ are each optionally substituted with 1, 2, 3, or4 independently selected R^(M) substituents; R⁵ is selected from H,halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl,C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkylof R⁵ are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(M) substituents; R⁷ is selected from H, halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; R⁸ is selected from H,halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, —C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a8), SR^(a8), NHOR^(a8),C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)NR^(c8)(OR^(a8)), C(O)OR^(a8),OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8), NR^(c8)NR^(c8)R^(d8),NR^(c8)C(O)R^(b8), NR^(c8)C(O)OR^(a8), NR^(c8)C(O)NR^(c8)R^(d8),C(═NR^(e8))R^(b8), C(═NR^(e8))NR^(c8)R^(d8), C(═NOR^(e8))R^(b8),C(═NOR^(e8))OR^(b8), NR^(c8)C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))R^(b8), NR^(c8)S(O)R^(b8), NR^(c8)S(O)NR^(c8)R^(d8),NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)(═NR^(e8))R^(b8),NR^(c8)S(O)₂NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8), S(O)₂R^(b8),S(O)₂NR^(c8)R^(d8), OS(O)(═NR^(e8))R^(b8), and OS(O)₂R^(b8), wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R⁸ are each optionally substituted with 1, 2, 3, or 4independently selected R^(8A) substituents; each R^(a8), R^(c8), andR^(d8) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a8),R^(c8) and R^(d8) are each optionally substituted with 1, 2, 3, or 4independently selected R^(8A) substituents; or, any R^(c8) and R^(d8)attached to the same N atom, together with the N atom to which they areattached, form a 5-10 membered heteroaryl or a 4-10 memberedheterocycloalkyl group, wherein the 5-10 membered heteroaryl or 4-10membered heterocycloalkyl group is optionally substituted with 1, 2, 3,or 4 independently selected R^(8A) substituents; each R^(b8) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(8A)substituents; each R^(c8) is independently selected from H, OH, CN, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-; each R^(8A) is independently selectedfrom halo, oxo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a81), SR^(a81), NHOR^(a81),C(O)R^(b81), C(O)NR^(c81)R^(d81), C(O)NR^(c81)(OR^(a81)), C(O)OR^(a81),OC(O)R^(b81), OC(O)NR^(c81)R^(d81), NR^(c81)R^(d81),NR^(c81)NR^(c81)R^(d81), NR^(c81)C(O)R^(b81), NR^(c81)C(O)OR^(b81),NR^(c81)C(O)NR^(c81)R^(d81), C(═NR^(e81))R^(b81),C(═NR^(e81))NR^(c81)R^(d81), C(═NOR^(a81))R^(b81),C(═NOR^(a81))OR^(a81), NR^(c81)C(═NR^(e81))NR^(c81)R^(d81),NR^(c81)C(═NR^(e81))R^(b81), NR^(c81)S(O)R^(b81),NR^(c81)S(O)NR^(c81)R^(d81), NR^(c81)S(O)₂R^(b81),NR^(c81)S(O)(═NR^(e81))R^(b81), NR^(c81)S(O)₂NR^(c81)R^(d81),S(O)R^(b81), S(O)NR^(c81)R^(d81), S(O)₂R^(b81), S(O)₂NR^(c81)R^(d81),OS(O)(═NR^(e81))R^(b81), and OS(O)₂R^(b81), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(8A) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(M)substituents; each R^(a81), R^(c81), and R^(d81) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a81), R^(c81) andR^(d81) are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(M) substituents; or, any R^(c81) and R^(d81) attached to thesame N atom, together with the N atom to which they are attached, form a5-10 membered heteroaryl or a 4-10 membered heterocycloalkyl group,wherein the 5-10 membered heteroaryl or 4-10 membered heterocycloalkylgroup is optionally substituted with 1, 2, 3, or 4 independentlyselected R^(M) substituents; each R^(b81) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b81) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(M)substituents; each R^(c81) is independently selected from H, OH, CN,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-; L¹ is C₁₋₃ alkyl; Cy¹ isphenyl or 5-6 membered heteroaryl, wherein the phenyl or 5-6 memberedheteroaryl are each optionally substituted with 1, 2, 3, or 4independently selected R¹ substituents; each R¹ is independentlyselected from halo, oxo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a11), SR^(a11), NHOR^(a11),C(O)R^(b11), C(O)NR^(c11)R^(d11), C(O)NR^(c11)(OR^(a11)), C(O)OR^(a11),OC(O)R^(b11), OC(O)NR^(c11)R^(d11), NR^(c11)R^(d11),NR^(c11)NR^(c11)R^(d11), NR^(c11)C(O)R^(b11), NR^(c11)C(O)OR^(a11),NR^(c11)C(O)NR^(c11)R^(d11), C(═NR^(e11))R^(b11),C(═NR^(e11))NR^(c11)R^(d11), NR^(c11)C(═NR^(e11))NR^(c11)R^(d11),NR^(c11)C(═NR^(e11))R^(b11), NR^(c11)S(O)R^(b11),NR^(c11)S(O)NR^(c11)R^(d11), NR^(c11)S(O)₂R^(b11),NR^(c11)S(O)(═NR^(e11))R^(b11), NR^(c11)S(O)₂NR^(c11)R^(d11),S(O)R^(b11), S(O)NR^(c11)R^(d11), S(O)₂R^(b11), S(O)NR^(c11)R^(d11),OS(O)(═NR^(e11))R^(b11), and OS(O)₂R^(b11), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R¹ are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(11A)substituents; each R^(a11), R^(c11), and R^(d11) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a11), R^(c11) andR^(d11) are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(11A) substituents; or, any R^(c11) and R^(d11) attached tothe same N atom, together with the N atom to which they are attached,form a 5-10 membered heteroaryl or a 4-10 membered heterocycloalkylgroup, wherein the 5-10 membered heteroaryl or 4-10 memberedheterocycloalkyl group is optionally substituted with 1, 2, 3, or 4independently selected R^(11A) substituents; each R^(b11) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b11) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(11A)substituents; each R^(e11) is independently selected from H, OH, CN,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-; each R^(11A) isindependently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl,4-7 membered heterocycloalkyl, CN, NO₂, OR^(a111),C(O)NR^(c111)R^(d111), C(O)OR^(a111), NR^(c111)R^(d111),S(O)NR^(c111)R^(d111), S(O)₂R^(b111), S(O)₂NR^(c111)R^(d111), andOS(O)₂R^(b111), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl of R^(11A) are each optionally substituted with 1, 2,3, or 4 independently selected R^(M) substituents; each R^(a111),R^(c111), and R^(d111) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a111), R^(c111) andR^(d111) are each optionally substituted with 1, 2, 3, or 4independently selected R^(M) substituents; or, any R^(c111) and R^(d111)attached to the same N atom, together with the N atom to which they areattached, form a 5-6 membered heteroaryl or a 4-7 memberedheterocycloalkyl group, wherein the 5-6 membered heteroaryl or 4-7membered heterocycloalkyl group is optionally substituted with 1, 2, 3,or 4 independently selected R^(M) substituents; each R^(b111) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b111) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents; R¹² is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a12),SR^(a12), NHOR^(a12), C(O)R^(b12), C(O)NR^(c12)R^(d12),C(O)NR^(c12)(OR^(a12)), C(O)OR^(a12), OC(O)R^(b12),OC(O)NR^(c12)R^(d12), NR^(c12)R^(d12), NR^(c12)NR^(c12)R^(d12),NR^(c12)C(O)R^(b12), NR^(c12)C(O)OR^(a12), NR^(c12)C(O)NR^(c12)R^(d12),C(═NR^(c12))R^(b12), C(═NR^(e12))NR^(c12)R^(d12),NR^(e12)C(═NR^(e12))NR^(c12)R^(d12), NR^(c12)C(═NR^(e12))R^(b12),NR^(c12)S(O)R^(b12), NR^(c12)S(O)NR^(c12)R^(d12), NR^(c12)S(O)₂R^(b12),NR^(c12)S(O)(═NR^(c12))R^(b12), NR^(c12)S(O)₂NR^(c12)R^(d12),S(O)R^(b12), S(O)NR^(c12)R^(d12), S(O)₂R^(b12), S(O)₂NR^(c12)R^(d12),OS(O)(═NR^(e12))R^(b12), and OS(O)₂R^(b12), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R² are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(12A)substituents; each R^(a12), R^(c12), and R^(d12) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a12), R^(c12) andR^(d12) are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(12A) substituents; or, any R^(c12) and R^(d12) attached tothe same N atom, together with the N atom to which they are attached,form a 5-10 membered heteroaryl or a 4-10 membered heterocycloalkylgroup, wherein the 5-10 membered heteroaryl or 4-10 memberedheterocycloalkyl group is optionally substituted with 1, 2, 3, or 4independently selected R^(12A) substituents; each R^(b12) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R² are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(12A)substituents; each R^(e12) is independently selected from H, OH, CN,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-; each R^(12A) isindependently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a121),SR^(a121), NHOR^(a121), C(O)R^(b121), C(O)NR^(c121)R^(d121),C(O)NR^(c121)(OR^(a121)), C(O)OR^(a121), OC(O)R^(b121),OC(O)NR^(c121)R^(d121), NR^(c121)R^(d121), NR^(c121)NR^(c121)R^(d121),NR^(c121)C(O)R^(b121), NR^(c121)C(O)OR^(a121),NR^(c121)C(O)NR^(c121)R^(d121), C(═NR^(e121))R^(b121),C(═NR^(e121))NR^(c121)R^(d121), NR^(c121)C(═NR^(e121))NR^(c121)R^(d121),NR^(c121)C(═NR^(e121))R^(b121), NR^(c121)S(O)R^(b121),NR^(c121)S(O)NR^(c121)R^(d121), NR^(c121)S(O)₂R^(b121),NR^(c121)S(O)(═NR^(e121))R^(b121), NR^(c121)S(O)₂NR^(c121)R^(d121),S(O)R^(b121), S(O)NR^(c121)R^(d121), S(O)₂R^(b121),S(O)₂NR^(c121)R^(d121), OS(O)(═NR^(e121))R^(b121), and OS(O)₂R^(b121);each R^(a121), R^(c121), and R^(d121) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-; or, any R^(c121) and R^(d121) attached tothe same N atom, together with the N atom to which they are attached,form a 5-10 membered heteroaryl or a 4-10 membered heterocycloalkylgroup; each R^(b121) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-; each R^(e121) is independently selected from H, OH, CN, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-; and each R^(M) is independently selectedfrom H, OH, halo, oxo, CN, C(O)OH, NH₂, NO₂, SF₅, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-.
 47. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein: W is CR⁷, N, or NR⁷;X is CR⁸ or C(O); Y is CH; Z is CH; n is 0, 1, or 2; each R² isindependently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl; R³ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; R⁵ is selected from H, halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R⁵ are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents; R⁷ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl; R⁸ is selected from H, halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,—C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, and OR⁸, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁸ are each optionally substituted with1, 2, 3, or 4 independently selected R^(8A) substituents; each R^(a8) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl; each R^(8A) is independently selected from halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and CN; L¹ is C₁₋₃alkyl; Cy¹ is phenyl or 5-6 membered heteroaryl, wherein the phenyl or5-6 membered heteroaryl are each optionally substituted with 1, 2, 3, or4 independently selected R¹¹ substituents; each R¹¹ is independentlyselected from halo, oxo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a11), SR^(a11), NHOR^(a11),C(O)R^(b11), C(O)NR^(c11)R^(d11), C(O)NR^(c11)(OR^(a11)), C(O)OR^(a11),OC(O)R^(b11), OC(O)NR^(c11)R^(d11), NR^(c11)R^(d11),NR^(c11)NR^(c11)R^(d11), NR^(c11)C(O)R^(b11), NR^(c11)C(O)OR^(a11),NR^(c11)C(O)NR^(c11)R^(d11), C(═NR^(e11))R^(b11),C(═NR^(e11))NR^(c11)R^(d11), NR^(c11)C(═NR^(e11))NR^(c11)R^(d11),NR^(c11)C(═NR^(e11))R^(b11), NR^(c11)S(O)R^(b11),NR^(c11)S(O)NR^(c11)R^(d11), NR^(c11)S(O)₂R^(b11),NR^(c11)S(O)(═NR^(e11))R^(b11), NR^(c11)S(O)₂NR^(c11)R^(d11),S(O)R^(b11), S(O)NR^(c11)R^(d11), S(O)₂R^(b11), S(O)NR^(c11)R^(d11),OS(O)(═NR^(e11))R^(b11), and OS(O)₂R^(b11), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R¹¹ are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(11A)substituents; each R^(a11), R^(c11), and R^(d11) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a11), R^(c11) andR^(d11) are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(11A) substituents; or, any R^(c11) and R^(d11) attached tothe same N atom, together with the N atom to which they are attached,form a 5-10 membered heteroaryl or a 4-10 membered heterocycloalkylgroup, wherein the 5-10 membered heteroaryl or 4-10 memberedheterocycloalkyl group is optionally substituted with 1, 2, 3, or 4independently selected R^(11A) substituents; each R^(b11) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b11) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(11A)substituents; each R^(e11) is independently selected from H, OH, CN,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-; each R^(11A) isindependently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl,4-7 membered heterocycloalkyl, CN, NO₂, OR^(a111),C(O)NR^(c111)R^(d111), C(O)OR^(a111), NR^(c111)R^(d111),S(O)NR^(c111)R^(d111), S(O)₂R^(b111), S(O)₂NR^(c111)R^(d111), andOS(O)₂R^(b111), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl of R^(11A) are each optionally substituted with 1, 2,3, or 4 independently selected R^(M) substituents; each R^(a111),R^(c111), and R^(d111) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a111), R^(c111) andR^(d111) are each optionally substituted with 1, 2, 3, or 4independently selected R^(M) substituents; or, any R^(c111) and R^(d111)attached to the same N atom, together with the N atom to which they areattached, form a 5-6 membered heteroaryl or a 4-7 memberedheterocycloalkyl group, wherein the 5-6 membered heteroaryl or 4-7membered heterocycloalkyl group is optionally substituted with 1, 2, 3,or 4 independently selected R^(M) substituents; each R^(b111) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b111) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents; R¹² is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a12),SR^(a12), NHOR^(a12), C(O)R^(b12), C(O)NR^(c12)R^(d12),C(O)NR^(c12)(OR^(a12)), C(O)OR^(a12), OC(O)R^(b12),OC(O)NR^(c12)R^(d12), NR^(c12)R^(d12), NR^(c12)NR^(c12)R^(d12),NR^(c12)C(O)R^(b12), NR^(c12)C(O)OR^(a12), NR^(c12)C(O)NR^(c12)R^(a12),C(═NR^(c12))R^(b12), C(═NR^(e12))NR^(c12)R^(d12),NR^(c12)C(═NR^(e12))NR^(c12)R^(d12), NR^(c12)C(═NR^(e12))R^(b12),NR^(c12)S(O)R^(b12), NR^(c12)S(O)NR^(c12)R^(d12), NR^(c12)S(O)₂R^(b12),NR^(c12)S(O)(═NR^(e12))R^(b12), NR^(c12)S(O)₂NR^(c12)R^(d12),S(O)R^(b12), S(O)NR^(c12)R^(d12), S(O)₂R^(b12), S(O)₂NR^(c12)R^(d12),OS(O)(═NR^(e12))R^(b12), and OS(O)₂R^(b12), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R¹² are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(12A)substituents; each R^(a12), R^(c12), and R^(d12) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a12), R^(c12) andR^(d12) are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(12A) substituents; or, any R^(c12) and R^(d12) attached tothe same N atom, together with the N atom to which they are attached,form a 5-10 membered heteroaryl or a 4-10 membered heterocycloalkylgroup, wherein the 5-10 membered heteroaryl or 4-10 memberedheterocycloalkyl group is optionally substituted with 1, 2, 3, or 4independently selected R^(12A) substituents; each R^(b12) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R² are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(12A)substituents; each R^(e12) is independently selected from H, OH, CN,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-; each R^(12A) isindependently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a121),SR^(a121), NHOR^(a121), C(O)R^(b121), C(O)NR^(c121)R^(d121),C(O)NR^(c121)(OR^(a121)), C(O)OR^(a121), OC(O)R^(b121),OC(O)NR^(c121)R^(d121), NR^(c121)R^(d121), NR^(c121)NR^(c121)R^(d121),NR^(c121)C(O)R^(b121), NR^(c121)C(O)OR^(a121),NR^(c121)C(O)NR^(c121)R^(d121), C(═NR^(e121))R^(b121),C(═NR^(e121))NR^(c121)R^(d121), NR^(c121)C(═NR^(e121))NR^(c121)R^(d121),NR^(c121)C(═NR^(e121))R^(b121), NR^(c121)S(O)R^(b121),NR^(c121)S(O)NR^(c121)R^(d121), NR^(c121)S(O)₂R^(b121),NR^(c121)S(O)(═NR^(e121))R^(b121), NR^(c121)S(O)₂NR^(c121)R^(d121),S(O)R^(b121), S(O)NR^(c121)R^(d121), S(O)₂R^(b121),S(O)₂NR^(c121)R^(d121), OS(O)(═NR^(e121))R^(b121), and OS(O)₂R^(b121);each R^(a121), R^(c121), and R^(d121) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-; or, any R^(c121) and R^(d121) attached tothe same N atom, together with the N atom to which they are attached,form a 5-10 membered heteroaryl or a 4-10 membered heterocycloalkylgroup; each R^(b121) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-; each R^(e121) is independently selected from H, OH, CN, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-; and each R^(M) is independently selectedfrom H, OH, halo, oxo, CN, C(O)OH, NH₂, NO₂, SF₅, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-.
 48. The compound of claim 1, wherein thecompound of Formula I is a compound of Formula II:

or a pharmaceutically acceptable salt thereof.
 49. The compound of claim1, wherein the compound of Formula I is a compound of Formula III:

or a pharmaceutically acceptable salt thereof.
 50. The compound of claim1, wherein the compound of Formula I is a compound of Formula IV:

or a pharmaceutically acceptable salt thereof.
 51. The compound of claim1, wherein the compound of Formula I is a compound of Formula V:

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3,4, or
 5. 52. The compound of claim 1, wherein the compound of Formula Iis a compound of Formula VI:

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3,4, or
 5. 53. The compound of claim 1, wherein the compound of Formula Iis a compound of Formula VII:

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3,4, or
 5. 54. The compound of claim 1, which is selected from:(8aR,11R)-10-(bis(4-fluorophenyl)methyl)-5,7,11-trimethyl-6,8-dioxo-5,7,8,8a,9,10,11,12-octahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-2-carbonitrile;(8aR,11R)-10-(bis(4-fluorophenyl)methyl)-7-(2-methoxyethyl)-5,11-dimethyl-6,8-dioxo-5,7,8,8a,9,10,11,12-octahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-2-carbonitrile;(2R,4aR)-3-(bis(4-fluorophenyl)methyl)-2,6,8-trimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinoline-5,7-dione;(8aR,11R)-10-(bis(4-fluorophenyl)methyl)-2-fluoro-5,7,11-trimethyl-5,7,9,10,11,12-hexahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-6,8(8aH)-dione;(8aR,11R)-10-(bis(4-fluorophenyl)methyl)-2,5,7,11-tetramethyl-5,7,9,10,11,12-hexahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-6,8(8aH)-dione;2-((8aR,11R)-10-(bis(4-fluorophenyl)methyl)-5,7,11-trimethyl-6,8-dioxo-5,7,8,8a,9,10,11,12-octahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridin-2-yl)acetonitrile;(8aR,11R)-10-(bis(4-fluorophenyl)methyl)-2-methoxy-5,7,11-trimethyl-5,7,9,10,11,12-hexahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-6,8(8aH)-dione;(8aR,11R)-10-(bis(4-fluorophenyl)methyl)-5,7,11-trimethyl-2-(1-methyl-1H-pyrazol-4-yl)-5,7,9,10,11,12-hexahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-6,8(8aH)-dione;and(8aR,11R)-10-(bis(4-fluorophenyl)methyl)-5,7,11-trimethyl-5,7,9,10,11,12-hexahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-2,6,8(8aH)-trione;or a pharmaceutically acceptable salt thereof.
 55. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein the compoundis deuterated.
 56. A pharmaceutical composition, comprising a compoundof claim 1, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.
 57. A method of inhibiting anactivity of a diacylglycerol kinase, comprising contacting the kinasewith a compound of claim 1, or a pharmaceutically acceptable saltthereof.
 58. A method of treating cancer in a patient in need thereof,the method comprising administering to the patient a therapeuticallyeffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof.
 59. The method of claim 58, wherein the canceris non-small cell lung cancer, bladder urothelial carcinoma, esophagealcarcinoma, stomach adenocarcinoma, mesothelioma, liver hepatocellularcarcinoma, diffuse large B cell lymphoma, kidney renal clear cellcarcinoma, head and neck squamous cell carcinoma, cholangiocarcinoma,cervical squamous cell carcinoma, endocervical adenocarcinoma, andmelanoma.
 60. The method of claim 59, wherein the melanoma is metastaticmelanoma.